MEK Inhibitors and Methods of Their Use

ABSTRACT

Disclosed are compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof. Such compounds are MEK inhibitors and are useful in the treatment of proliferative diseases, such as cancer. Also disclosed are pharmaceutical compositions containing such compounds as well as methods of using the compounds and compositions of the invention in the treatment of cancer.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to certain inhibitors of MEK which are useful inthe treatment of hyperproliferative diseases, such as cancer, inmammals. This invention also relates to a method of using such compoundsin the treatment of hyperproliferative diseases in mammals, especiallyhumans, and to pharmaceutical compositions containing such compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

The Applicants claim priority under 35 U.S.C. 119(c) to copendingProvisional Applications No. 60/724,578 filed on Oct. 7, 2005 and No.60/802,840 filed on May 23, 2006, the disclosures of which areincorporated herein by reference in its entirety.

State of the Art

Improvements in the specificity of agents used to treat cancer is ofconsiderable interest because of the therapeutic benefits which would berealized if the side effects associated with the administration of theseagents could be reduced. Traditionally, dramatic improvements in thetreatment of cancer are associated with identification of therapeuticagents acting through novel mechanisms.

Protein kinases are enzymes that catalyze the phosphorylation ofproteins, in particular, hydroxy groups on tyrosine, serine andthreonine residues of proteins. The consequences of this seeminglysimple activity are staggering; cell differentiation and proliferation;i.e., virtually all aspects of cell life in one-way or another depend onprotein kinase activity. Furthermore, abnormal protein kinase activityhas been related to a host of disorders, ranging from relativelynon-life threatening diseases such as psoriasis to extremely virulentdiseases such as glioblastoma (brain cancer).

Protein kinases can be categorized as receptor type or non-receptortype. Receptor-type tyrosine kinases have an extracellular, atransmembrane, and an intracellular portion, while non-receptor typetyrosine kinases are wholly intracellular. They are comprised of a largenumber of transmembrane receptors with diverse biological activity. Infact, about 20 different subfamilies of receptor-type tyrosine kinaseshave been identified. One tyrosine kinase subfamily, designated the HERsubfamily, is comprised of EGFR (HER1), HER2, HER3, and HER4. Ligands ofthis subfamily of receptors identified so far include epithelial growthfactor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and heregulin.Another subfamily of these receptor-type tyrosine kinases is the insulinsubfamily, which includes INS-R, IGF-IR, and IR-R. The PDGF subfamilyincludes the PDGF-alpha and beta receptors, CSFIR, c-kit and FLK-II. Inaddition, there is the FLK family, which is comprised of the kinaseinsert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liverkinase-4 (FLK-4) and the fins-like tyrosine kinase-1 (flt-1). The PDGFand FLK families are usually considered together due to the similaritiesof the two groups. For a detailed discussion of the receptor-typetyrosine kinases, see Plowman et al., DN&P 7(6): 334-339, 1994, which ishereby incorporated by reference.

The non-receptor type of tyrosine kinases is also comprised of numeroussubfamilies, including Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak,Jak, Ack, and LIMK. Each of these subfamilies is further sub-dividedinto varying receptors. For example, the Src subfamily is one of thelargest and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk.The Src subfamily of enzymes has been linked to oncogenesis. For a moredetailed discussion of the non-receptor type of tyrosine kinases, seeBolen, Oncogene, 8:2025-2031 (1993), which is hereby incorporated byreference.

Since protein kinases and their ligands play critical roles in variouscellular activities, deregulation of protein kinase enzymatic activitycan lead to altered cellular properties, such as uncontrolled cellgrowth associated with cancer. In addition to oncological indications,altered kinase signaling is implicated in numerous other pathologicaldiseases. These include, but are not limited to: immunologicaldisorders, cardiovascular diseases, inflammatory diseases, anddegenerative diseases. Therefore, both receptor and non-receptor proteinkinases are attractive targets for small molecule drug discovery.

One particularly attractive goal for therapeutic use of kinasemodulation relates to oncological indications. For example, modulationof protein kinase activity for the treatment of cancer has beendemonstrated successfully with the FDA approval of Gleevec® (imatinibmesylate, produced by Novartis Pharmaceutical Corporation of EastHanover, N.J.) for the treatment of Chronic Myeloid Leukemia (CML) andgastrointestinal stroma cancers. Gleevec is a selective Abl kinaseinhibitor.

Modulation (particularly inhibition) of cell proliferation andangiogenesis, two key cellular processes needed for tumor growth andsurvival (Matter A. Drug Disc Technol 2001 6, 1005-1024), is anattractive goal for development of small-molecule drugs. Anti-angiogenictherapy represents a potentially important approach for the treatment ofsolid tumors and other diseases associated with dysregulatedvascularization, including ischemic coronary artery disease, diabeticretinopathy, psoriasis and rheumatoid arthritis. As well, cellantiproliferative agents are desirable to slow or stop the growth oftumors.

One particularly attractive target for small-molecule modulation, withrespect to antiangiogenic and antiproliferative activity is MEK.Inhibition of MEK1 (MAPK/ERK Kinase) is a promising strategy to controlthe growth of tumors that are dependent on aberrant ERK/MAPK pathwaysignaling (Solit et al., 2006; Wellbrock et al., 2004). The MEK-ERKsignal transduction cascade is a conserved pathway which regulates cellgrowth, proliferation, differentiation, and apoptosis in response togrowth factors, cytokines, and hormones. This pathway operatesdownstream of Ras which is often upregulated or mutated in human tumors.It has been demonstrated that MEK is a critical effector of Rasfunction. The ERK/MAPK pathway is upregulated in 30% of all tumors andoncogenic activating mutations in K-Ras and B-Raf have been identifiedin 22% and 18% of all cancers respectively (Allen et al., 2003; BamfordS, 2004; Davies et al., 2002; Malumbres and Barbacid, 2003). A largeportion of human cancers, including 66% (B-Rat) of malignant melanomas,60% (K-Ras) and 4% (B-Raf) of pancreatic cancers, 50% of colorectalcancers (colon, in particular, K-Ras: 30%, B-Raf: 15%), 20% (K-Ras) oflung cancers, 27% (B-Rat) papillary and anaplastic thyroid cancer, and10-20% (B-Rat) of endometriod ovarian cancers, harbor activating Ras andRaf mutations. It has been shown that inhibition of the ERK pathway, andin particular inhibition of MEK kinase activity, results inanti-metastatic and anti-angiogenic effects largely due to a reductionof cell-cell contact and motility as well as downregulation of vascularendothelial growth factor (VEGF) expression. Furthermore, expression ofdominant negative MEK, or ERK reduced the transforming ability of mutantRas as seen in cell culture and in primary and metastatic growth ofhuman tumor xenografts in vivo. Therefore, the MEK-ERK signaltransduction pathway is an appropriate pathway to target for therapeuticintervention.

Accordingly, the identification of small-molecule compounds thatspecifically inhibit, regulate and/or modulate the signal transductionof kinases, particularly MEK, is desirable as a means to treat orprevent disease states associated with cancer and is an object of thisinvention.

SUMMARY OF THE INVENTION

The following only summarizes certain aspects of the invention and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below. All references cited inthis specification are hereby incorporated by reference in theirentirety. In the event of a discrepancy between the express disclosureof this specification and the references incorporated by reference, theexpress disclosure of this specification shall control.

This invention provides compounds that inhibit, regulate and/or modulatethe signal transduction of kinases, particularly MEK. The compounds ofthe invention are certainazetidin-1-yl(2-(2-fluorophenylamino)cyclic)methanones derivatives thatare useful in the treatment of hyperproliferative diseases, such ascancer, in humans. This invention also provides methods of making thecompound, methods of using such compounds in the treatment ofhyperproliferative diseases in humans and to pharmaceutical compositionscontaining such compounds.

In one aspect, the invention provides a compound of Formula I:

or a pharmaceutically acceptable salt or solvate, thereof, wherein A, X,R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined in Group A, Group B, GroupC, or Group D:

Group A:

-   A is arylene optionally substituted with one, two, three or four    groups selected from R¹⁰, R¹², R¹⁴, and R¹⁶ where R¹⁰, R¹², R¹⁴ and    R¹⁶ are independently hydrogen, alkyl, alkenyl, alkynyl, halo,    haloalkoxy, hydroxy, alkoxy, amino, alkylamino, dialkylamino,    haloalkyl, —NHS(O)₂R⁸, —CN, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′) and    —NR⁸C(O)R^(8′);-   X is alkyl, halo, haloalkyl, or haloalkoxy;-   R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen, halo, nitro,    —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′),    —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),    —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),    —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵SC(═NH)(N(R^(25a))(CN)),    —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl,    alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl, where    the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and    heterocycloalkyl are independently optionally substituted with one,    two, three, four, five, six or seven groups independently selected    from halo, alkyl, haloalkyl, nitro, optionally substituted    cycloalkyl, optionally substituted heterocycloalkyl, optionally    substituted aryl, optionally substituted arylalkyl, optionally    substituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN,    —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or one of    R¹ and R² together with the carbon to which they are attached, R³    and R⁴ together with the carbon to which they are attached, and R⁵    and R⁶ together with the carbon to which they are attached form C(O)    or C(═NOH);-   m is 0, 1, or 2;-   R⁷ is hydrogen, halo or alkyl;-   R⁸, R^(8′) and R^(8″) are independently selected from hydrogen,    hydroxy, optionally substituted alkoxy, alkyl, alkenyl, alkynyl,    aryl, cycloalkyl, heteroaryl, and heterocycloalkyl; where the alkyl,    alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl    are independently optionally substituted with one, two three, four,    or five groups independently selected from alkyl, halo, hydroxy,    hydroxyalkyl, optionally substituted alkoxy, alkoxyalkyl, haloalkyl,    carboxy, alkoxycarbonyl, alkenyloxycarbonyl, optionally substituted    cycloalkyl, optionally substituted cycloalkyloxycarbonyl, optionally    substituted aryl, optionally substituted aryloxy, optionally    substituted aryloxycarbonyl, optionally substituted arylalkyl,    optionally substituted arylalkyloxy, optionally substituted    arylalkyloxycarbonyl, nitro, cyano, optionally substituted    heterocycloalkyl, optionally substituted heteroaryl, —S(O)_(n)R³¹    (where n is 0, 1, or 2 and R³¹ is optionally substituted alkyl,    optionally substituted aryl, optionally substituted    heterocycloalkyl, or optionally substituted heteroaryl),    —NR³⁴SO₂R^(34a) (where R³⁴ is hydrogen or alkyl and R^(34a) is    alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl),    —SO₂NR³⁵R^(35a) (where R³⁵ is hydrogen or alkyl and R^(35a) is    alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl),    —NR³²C(O)R^(32a) (where R³² is hydrogen or alkyl and R^(32a) is    alkyl, alkenyl, alkoxy, or cycloalkyl), —NR³⁰R^(30′) (where R³⁰ and    R^(30′) are independently hydrogen, alkyl, or hydroxyalkyl), and    —C(O)NR³³R^(33a) (where R³³ is hydrogen or alkyl and R^(33a) is    alkyl, alkenyl, alkynyl, or cycloalkyl);-   R⁹ is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and    heterocycloalkyl; where the alkyl, alkenyl, alkynyl, aryl,    cycloalkyl, heteroaryl, and heterocycloalkyl are independently    optionally substituted with one, two, three, four, or five groups    selected from halo, hydroxy, alkyl, haloalkyl, haloalkoxy, amino,    alkylamino, and dialkylamino;-   R²⁵ and R^(25b) are independently hydrogen, alkyl, alkenyl,    optionally substituted cycloalkyl, or optionally substituted aryl;    and-   R²⁵ is hydrogen, alkyl, or alkenyl;

Group B:

-   A is heteroarylene optionally substituted with one, two, three, or    four groups selected from R¹⁰, R¹², R¹⁴, R¹⁶ and R¹⁹ where R¹⁰, R¹²,    R¹⁴ and R¹⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,    halo, haloalkoxy, hydroxy, alkoxy, cyano, amino, alkylamino,    dialkylamino, haloalkyl, alkylsulfonylamino, alkylcarbonyl,    alkenylcarbonyl, alkoxycarbonyl, alkenyloxycarbonyl, aminocarbonyl,    alkylaminocarbonyl, dialkylaminocarbonyl, or alkylcarbonylamino;    where R¹⁹ is hydrogen, alkyl, or alkenyl; and where each alkyl and    alkenyl, either alone or as part of another group within R¹⁰, R¹²,    R¹⁴, R¹⁶, and R¹⁹ is independently optionally substituted with halo,    hydroxy, or alkoxy;-   X is alkyl, halo, haloalkyl, or haloalkoxy;-   R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen, halo, nitro,    —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′),    —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),    —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),    —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵SC(═NH)(N(R^(25a))(CN)),    —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl,    alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl, where    the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and    heterocycloalkyl are independently optionally substituted with one,    two, three, four, five, six or seven groups independently selected    from halo, alkyl, haloalkyl, nitro, optionally substituted    cycloalkyl, optionally substituted heterocycloalkyl, optionally    substituted aryl, optionally substituted arylalkyl, optionally    substituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN,    —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or one of    R¹ and R² together with the carbon to which they are attached, R³    and R⁴ together with the carbon to which they are attached, and R⁵    and R⁶ together with the carbon to which they are attached form C(O)    or C(═NOH);-   m is 1 or 2;-   R⁷ is hydrogen, halo or alkyl; and-   R⁸, R^(8′) and R^(8″) are independently selected from hydrogen,    hydroxy, optionally substituted alkoxy, alkyl, haloalkyl, alkenyl,    alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, where    the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and    heterocycloalkyl are independently optionally substituted with one,    two three, four, or five groups independently selected from alkyl,    halo, hydroxy, hydroxyalkyl, optionally substituted alkoxy,    alkoxyalkyl, haloalkyl, carboxy, carboxy ester, nitro, cyano,    —S(O)_(n)R³¹ (where n is 0, 1, or 2 and R³¹ is optionally    substituted alkyl, optionally substituted aryl, optionally    substituted cycloalkyl, optionally substituted heterocycloalkyl, or    optionally substituted heteroaryl), —NR³⁶S(O)₂R^(36a) (where R³⁶ is    hydrogen, alkyl, or alkenyl and R^(36a) is alkyl, alkenyl,    optionally substituted aryl, optionally substituted cycloalkyl,    optionally substituted heterocycloalkyl, or optionally substituted    heteroaryl), —S(O)₂NR³⁷R^(37a) (where R³⁷ is hydrogen, alkyl, or    alkenyl and R^(37a) is alkyl, alkenyl, optionally substituted aryl,    optionally substituted cycloalkyl, optionally substituted    heterocycloalkyl, or optionally substituted heteroaryl), optionally    substituted cycloalkyl, optionally substituted heterocycloalkyl,    optionally substituted aryl, optionally substituted arylalkyl,    optionally substituted aryloxy, optionally substituted arylalkyloxy,    optionally substituted heteroaryl, —NHC(O)R³² (where R³² is alkyl,    alkenyl, alkoxy, or cycloalkyl) and —NR³⁰R^(30′) (where R³⁰ and    R^(30′) are independently hydrogen, alkyl, or hydroxyalkyl), and    —C(O)NHR³³ (where R³³ is alkyl, alkenyl, alkynyl, or cycloalkyl);

Group C: A is

-   where R¹⁰ is hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkoxy,    hydroxy, alkoxy, amino, alkylamino, dialkylamino, haloalkyl,    —NHS(O)₂R⁸, —CN, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′) and    —NR⁸C(O)R^(8′);-   R^(10a) is hydrogen, alkyl, or alkenyl;-   Y¹ is ═CH— or ═N—;-   X is alkyl, halo, haloalkyl, or haloalkoxy;-   R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen, halo, nitro,    —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′),    —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),    —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),    —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵SC(═NH)(N(R^(25a))(CN)),    —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl,    alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl, where    the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and    heterocycloalkyl are independently optionally substituted with one,    two, three, four, five, six or seven groups independently selected    from halo, alkyl, haloalkyl, nitro, optionally substituted    cycloalkyl, optionally substituted heterocycloalkyl, optionally    substituted aryl, optionally substituted arylalkyl, optionally    substituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN,    —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or one of    R¹ and R² together with the carbon to which they are attached, R³    and R⁴ together with the carbon to which they are attached, and R⁵    and R⁶ together with the carbon to which they are attached form C(O)    or C(═NOH);-   m is 1 or 2;-   R⁷ is hydrogen, halo or alkyl; and-   R⁸, R^(8′) and R_(8″) are independently selected from hydrogen,    hydroxy, optionally substituted alkoxy, alkyl, haloalkyl, alkenyl,    alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, where    the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and    heterocycloalkyl am independently optionally substituted with one,    two three, four, or five groups independently selected from alkyl,    halo, hydroxy, hydroxyalkyl, optionally substituted alkoxy,    alkoxyalkyl, haloalkyl, carboxy, carboxy ester, nitro, cyano,    —S(O)_(n)R³¹ (where n is 0, 1, or 2 and R³¹ is optionally    substituted alkyl, optionally substituted aryl, optionally    substituted cycloalkyl, optionally substituted heterocycloalkyl, or    optionally substituted heteroaryl), —NR³⁶S(O)₂R³⁶ (where R³⁶ is    hydrogen, alkyl, or alkenyl and R^(36a) is alkyl, alkenyl,    optionally substituted aryl, optionally substituted cycloalkyl,    optionally substituted heterocycloalkyl, or optionally substituted    heteroaryl), —S(O)₂NR³⁷R^(37a) (where R³⁷ is hydrogen, alkyl, or    alkenyl and R^(37a) is alkyl, alkenyl, optionally substituted aryl,    optionally substituted cycloalkyl, optionally substituted    heterocycloalkyl, or optionally substituted heteroaryl), optionally    substituted cycloalkyl, optionally substituted heterocycloalkyl,    optionally substituted aryl, optionally substituted arylalkyl,    optionally substituted aryloxy, optionally substituted arylalkyloxy,    optionally substituted heteroaryl, —NHC(O)R³² (where R³² is alkyl,    alkenyl, alkoxy, or cycloalkyl) and —NR³⁰R^(30′) (where R³⁰ and    R^(30′) are independently hydrogen, alkyl, or hydroxyalkyl), and    —C(O)NHR³³ (where R³³ is alkyl, alkenyl, alkynyl, or cycloalkyl); or

Group D: A is

-   R⁴⁰ and R^(40a) are independently hydrogen or alkyl;-   X is alkyl, halo, haloalkyl, or haloalkoxy,-   R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen, halo, nitro,    —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′),    —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),    —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),    —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵SC(═NH)(N(R^(25a))(CN)),    —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl,    alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl, where    the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and    heterocycloalkyl are independently optionally substituted with one,    two, three, four, five, six or seven groups independently selected    from halo, alkyl, haloalkyl, nitro, optionally substituted    cycloalkyl, optionally substituted heterocycloalkyl, optionally    substituted aryl, optionally substituted arylalkyl, optionally    substituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN,    —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or one of    R¹ and R² together with the carbon to which they are attached, R³    and R⁴ together with the carbon to which they are attached, and R⁵    and R⁶ together with the carbon to which they are attached form C(O)    or C(═NOH);-   m is 1 or 2;-   R⁷ is hydrogen, halo or alkyl; and-   R⁸, R^(8′) and R_(8″) are independently selected from hydrogen,    hydroxy, optionally substituted alkoxy, alkyl, haloalkyl, alkenyl,    alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, where    the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and    heterocycloalkyl are independently optionally substituted with one,    two three, four, or five groups independently selected from alkyl,    halo, hydroxy, hydroxyalkyl, optionally substituted alkoxy,    alkoxyalkyl, haloalkyl, carboxy, carboxy ester, nitro, cyano,    —S(O)_(n)R³¹ (where n is 0, 1, or 2 and R³¹ is optionally    substituted alkyl, optionally substituted aryl, optionally    substituted cycloalkyl, optionally substituted heterocycloalkyl, or    optionally substituted heteroaryl), —NR³⁶S(O)₂R^(36a) (where R³⁶ is    hydrogen, alkyl, or alkenyl and R^(36a) is alkyl, alkenyl,    optionally substituted aryl, optionally substituted cycloalkyl,    optionally substituted heterocycloalkyl, or optionally substituted    heteroaryl), —S(O)₂NR³⁷R^(37a) (where R³⁷ is hydrogen, alkyl, or    alkenyl and R^(37a) is alkyl, alkenyl, optionally substituted aryl,    optionally substituted cycloalkyl, optionally substituted    heterocycloalkyl, or optionally substituted heteroaryl), optionally    substituted cycloalkyl, optionally substituted heterocycloalkyl,    optionally substituted aryl, optionally substituted arylalkyl,    optionally substituted aryloxy, optionally substituted arylalkyloxy,    optionally substituted heteroaryl, —NHC(O)R³² (where R³² is alkyl,    alkenyl, alkoxy, or cycloalkyl) and —NR³⁰R^(30′) (where R³⁰ and    R^(30′) are independently hydrogen, alkyl, or hydroxyalkyl), and    —C(O)NHR³³ (where R³³ is alkyl, alkenyl, alkynyl, or cycloalkyl).

A second aspect of the Invention provides a pharmaceutical compositionwhich comprises a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier, excipient, or diluent.

In a third aspect, the invention is directed to a method of inhibitingMEK comprising administering to a patient a therapeutically effectiveamount of a compound of Formula I, or a pharmaceutically acceptable saltor solvate thereof, and optionally a pharmaceutically acceptablecarrier, excipient, or diluent.

In a fourth aspect, the invention comprises a method of inhibiting MEKin a cell, comprising contacting a cell with a compound of Formula I ora pharmaceutically acceptable salt or solvate therof, or with apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula I and a pharmaceutically acceptable carrier,excipient, or diluent.

A fifth aspect of the Invention provides a method for treating adisease, disorder, or syndrome which method comprises administering to apatient a compound of Formula I or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula I and apharmaceutically acceptable carrier, excipient, or diluent.

A sixth aspect of the invention is directed to a process of preparing acompound of Formula I, comprising:

(a) reacting an intermediate of formula 19:

where X¹ is OH or halo, specifically chloro or fluoro, and all othergroups are as defined in the Summary of the Invention for a compoundselected from Group A, Group B, Group C, and Group D; with anintermediate of formula 17:

where R¹, R², R³, R⁴, R⁵, and R⁶ are as defined in the Summary of theInvention for a compound selected from Group A, Group B, Group C, andGroup D; and

(b) optionally separating individual isomers; and

(c) optionally modifying any of the R¹, R², R³, R⁴, R⁵, and R⁶ groups.

A seventh aspect of the invention is directed to a process of preparingintermediates of formula 3, 4, 5, 6, 10, and 13, comprising:

-   -   (a) reacting an intermediate of formula 2(a):

with R⁴M (where R⁴M is a Grignard reagent or organometallic species andR⁴ is as defined in the Summary of the Invention for a compound of GroupA, Group B, Group C, or Group D); with R⁴′CH₂NO₂ (where R⁴′ is hydrogenor alkyl optionally substituted as described for R⁴ in the Summary ofthe Invention for a compound of Group A, Group B. Group C, or Group D);with R⁴′R⁴″C(O) (R⁴′ is alkyl optionally substituted as described for R⁴in the Summary of the Invention for a compound of Group A, Group B,Group C, or Group D and R⁴″ is hydrogen or R⁴′); with R′R″CHP(Ph)₃(where R′ and R″ are independently hydrogen, alkyl, alkenyl, aryl, orheteroaryl and the alkyl, alkenyl, aryl, and heteroaryl are optionallysubstituted as described for R⁴ in the Summary of the Invention for acompound of Group A, Group B, Group C, or Group D); with a chiraloxazolidinone auxiliary and subsequent treatment with a base, such aslithium hydroxide, in aqueous hydrogen peroxide; or with a N-protectedheterocycloalkyl group where P¹ is Boc and P² is CBz or P¹ is CBz and P²is Boc; to yield the intermediates of formula 3, 4, 5, 6, 12, and 13,respectively:

-   -   (b) optionally further reacting 6 with m-CPBA to form an epoxide        and further opening the epoxide with an amine of formula        NHR⁸R^(8′) to yield an intermediate of formula 8:

-   -   -   where P is a N-protecting group and R⁸ and R^(8′) are as            defined in the Summary of the Invention for a compound of            Group A, Group B, Group C, or Group D;

    -   (c) optionally further subjecting 10 to a Curtius rearrangement        and subsequent treatment to yield an intermediate of formula 12:

-   -   -   where P is a N-protecting group and R′ is an alkyl group            such as methyl or ethyl;

    -   (d) optionally further resolving individual isomers; and

    -   (e) optionally modifying any of the R¹, R², R³, R⁴, R⁵, and R⁶        groups.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions

The following abbreviations and terms have the indicated meaningsthroughout:

Abbreviation Meaning Ac acetyl br broad ° C. degrees Celsius CBZCarboBenZoxy = benzyloxycarbonyl d doublet dd doublet of doublet dtdoublet of triplet DAST (diethylamino)sulfur trifluoride DCMdichloromethane DIPEA N,N-diisopropylethylamine DMAP4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EDCI1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EI Electron Impactionization Et ethyl g gram(s) GC gas chromatography h or hr hour(s) HBTU2-(1H-benzotriazole-1-yl)-1,1,3,3-tetrarmethyluroniumhexafluorophosphate HOAc acetic acid HOBt hydroxybenzotriazole HPLC highpressure liquid chromatography L liter(s) LDA lithium diiospropylamideLHMDS lithium hexamethyldisilazide M molar or molarity m multiplet MCPBAmeta-chloroperbenzoic acid Me methyl mg milligram(s) MHz megahertz(frequency) min minute(s) mL milliliter(s) mM millimolar mmolmillimole(s) mol mole(s) MS mass spectral analysis N normal or normalitynM nanomolar NMM N-methylmorpholine NMR nuclear magnetic resonancespectroscopy PyBOP benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate q quartet RT room temperature s singlet s- secondaryt- tertiary t or tr triplet THF tetrahydrofuran μL microliter(s) μMmicromole(s) or micrornolar

The symbol “−” means a single bond, “=” means a double bond, “≡” means atriple bond, and “

” single bond and optionally a double bond. When chemical structures aredepicted or described, unless explicitly stated otherwise, all carbonsare assumed to have hydrogen substitution to conform to a valence offour.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to have hydrogen substitutionto conform to a valence of four. For example, in the structure on theleft-hand side of the schematic below there are nine hydrogens implied.The nine hydrogens are depicted in the right-hand structure. Sometimes aparticular atom in a structure is described in textual formula as havinga hydrogen or hydrogens as substitution (expressly defined hydrogen),for example, —CH₂CH₂—. It is understood by one of ordinary skill in theart that the aforementioned descriptive techniques are common in thechemical arts to provide brevity and simplicity to description ofotherwise complex structures.

If a group “R” is depicted as “floating” on a ring system, as forexample in the formula:

then, unless otherwise defined, a substituent “R” may reside on any atomof the ring system, assuming replacement of a depicted, implied, orexpressly defined hydrogen from one of the ring atoms, so long as astable structure is formed.

If a group “R” is depicted as floating on a fused ring system, as forexample in the formulae:

then, unless otherwise defined, a substituent “R” may reside on any atomof the used ring system, assuming replacement of a depicted hydrogen(for example the —NH— in the formula above), implied hydrogen (forexample as in the formula above, where the hydrogens are not shown butunderstood to be present), or expressly defined hydrogen (for examplewhere in the formula above, “X” equals ═CH—) from one of the ring atoms,so long as a stable structure is formed. In the example depicted, the“R” group may reside on either the 5-membered or the 6-membered ring ofthe fused ring system. In the formula depicted above, when y is 2 forexample, then the two “R's” may reside on any two atoms of the ringsystem, again assuming each replaces a depicted, implied, or expresslydefined hydrogen on the ring.

When a group “R” is depicted as existing on a ring system containingsaturated carbons, as for example in the formula:

where, in this example, “y” can be more than one, assuming each replacesa currently depicted, implied, or expressly defined hydrogen on thering; then, unless otherwise defined, where the resulting structure isstable, two “R's” may reside on the same carbon. A simple example iswhen R is a methyl group; there can exist a geminal dimethyl on a carbonof the depicted ring (an “annular” carbon). In another example, two R'son the same carbon, including that carbon, may form a ring, thuscreating a spirocyclic ring (a “spirocyclyl” group) structure with thedepicted ring as for example in the formula:

“Acyl” means a —C(O)R radical where R is optionally substituted alkyl,optionally substituted alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, orheterocycloalkylalkyl, as defined herein, e.g., acetyl, benzoyl,trifluoromethylcarbonyl, or 2-methoxyethylcarbonyl, and the like.

“Acylamino” means a —NRR′ group where R is acyl, as defined herein, andR′ is hydrogen or alkyl.

“Administration” and variants thereof (e.g., “administering” a compound)in reference to a compound of the invention means introducing thecompound or a prodrug of the compound into the system of the animal inneed of treatment. When a compound of the invention or prodrug thereofis provided in combination with one or more other active agents (e.g.,surgery, radiation, and chemotherapy, etc.), “administration” and itsvariants are each understood to include concurrent and sequentialintroduction of the compound or prodrug thereof and other agents.

“Alkenyl” means a means a linear monovalent hydrocarbon radical of oneto six carbon atoms or a branched monovalent hydrocarbon radical ofthree to 6 carbon atoms which radical contains at least one double bond,e.g., ethenyl, propenyl, 1-but-3-enyl, I-pent-3-enyl, 1-hex-5-enyl andthe like.

“Alkenylcarbonyl” means a —C(O)R group where R is alkenyl, as definedherein.

“Alkenyloxycarbonyl” means a —C(O)OR group where R is alkenyl, asdefined herein.

“Alkoxy” means an —OR group where R is alkyl group as defined herein.Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like.Lower-alkoxy refers to groups containing one to six carbons.

“Alkoxyalkyl” means an alkyl group, as defined herein, substituted withat least one, preferably one, two, or three, alkoxy groups as definedherein. Representative examples include methoxymethyl and the like.

“Alkoxycarbonyl” means a —C(O)OR group where R is alkyl as definedherein.

“Alkoxycarbonylamino” means a —NR′R″ group where R′ is hydrogen, alkyl,hydroxy, or alkoxy and R″ is alkoxycarbonyl, as defined herein.

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto eight carbon atoms or a branched saturated monovalent hydrocarbonradical of three to eight carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, butyl (including all isomeric forms), or pentyl (including allisomeric forms), and the like.

“Alkylamino” means a —NHR radical where R is alkyl as defined herein, oran N-oxide derivative, or a protected derivative thereof, e.g.,methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino,iso-butylamino, tert-butylamino, or methylamino-N-oxide, and the like.

“Alkylaminoalkyl” means an alkyl group substituted with one or twoalkylamino groups, as defined herein.

“Alkylaminocarbonyl” means a —C(O)R group where R is alkylamino, asdefined herein.

“Alkylcarbonyl” means a —C(O)R group where R is alkyl, as definedherein.

“Alkylcarbonylamino” means a —NRR′ group where R is hydrogen or alkyl asdefined herein and R′ is alkylcarbonyl, as defined herein.

“Alkylcarbonyloxy” means an —OC(O)R group where R is alkyl, as definedherein.

“Alkylsulfonylamino” means a —NRS(O)₂R′ group where R is hydrogen oralkyl as defined herein, and R′ is alkyl, as defined herein.

“Alkynyl” means a straight or branched hydrocarbon radical having from 2to 8 carbon atoms and at least one triple bond and includes ethynyl,propynyl, butynyl, pentyn-2-yl and the like.

“Aminoalkyl” means an alkyl group substituted with at least one,specifically one, two or three, amino groups.

“Aminocarbonyl” means a —C(O)NH₂ group.

“Aryl” means a monovalent six- to fourteen-membered, mono- orbi-carbocyclic ring, wherein the monocyclic ring is aromatic and atleast one of the rings in the bicyclic ring is aromatic. Unless statedotherwise, the valency of the group may be located on any atom of anyring within the radical, valency rules permitting. Representativeexamples include phenyl, naphthyl, and indanyl, and the like.

“Arylene” means a divalent six- to fourteen-membered, mono- orbi-carbocyclic ring, wherein the monocyclic ring is aromatic and atleast one of the rings in the bicyclic ring is aromatic. Representativeexamples include phenylene, naphthylene, and indanylene, and the like.

“Arylalkyl” means an alkyl group, as defined herein, substituted withone or two aryl groups, as defined herein. Examples include benzyl,phenethyl, and the like.

“Carboxy ester” means a —C(O)OR group where R is lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, aryl or arylalkyl, each of which isdefined herein. Representative examples include methoxycarbonyl,ethoxycarbonyl, and benzyloxycarbonyl, and the like.

“Cycloalkyl” means a monocyclic or fused bicyclic, saturated orpartially unsaturated (but not aromatic), monovalent hydrocarbon radicalof three to ten carbon ring atoms. Fused bicyclic hydrocarbon radicalincludes bridged ring systems. Unless stated otherwise, the valency ofthe group may be located on any atom of any ring within the radical,valency rules permitting. One or two ring carbon atoms may be replacedby a —C(O)—, —C(S)—, or —C(═NH)— group. More specifically, the termcycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexyl, or cyclohex-3-enyl, and the like.

“Dialkylamino” means a —NRR′ radical where R and R′ are alkyl as definedherein, or an N-oxide derivative, or a protected derivative thereof,e.g., dimethylamino, diethylamino, N,N-methylpropylamino orN,N-methylethylamino, and the like.

“Dialkylaminoalkyl” means an alkyl group substituted with one or twodialkylamino groups, as defined herein.

“Dialkylaminocarbonyl” means a —C(O)R group where R is dialkylamino, asdefined herein.

“Fused-polycyclic” or “fused ring system” means a polycyclic ring systemthat contains fused rings and, unless otherwise indicated, can containbridged rings; that is, where two rings have more than one shared atomin their ring structures. In this application, fused-polycyclics andfused ring systems are not necessarily all aromatic ring systems.Typically, but not necessarily, fused-polycyclics share a vicinal set ofatoms, for example naphthalene or 1,2,3,4-tetrahydro-naphthalene. Aspiro ring system is not a fused-polycyclic by this definition, butfused polycyclic ring systems of the invention may themselves have spirorings attached thereto via a single ring atom of the fused-polycyclic.In some examples, as appreciated by one of ordinary skill in the art,two adjacent groups on an aromatic system may be fused together to forma ring structure. The fused ring structure may contain heteroatoms andmay be optionally substituted with one or more groups. It shouldadditionally be noted that saturated carbons of such fused groups (i.e.saturated ring structures) can contain two substitution groups.

“Haloalkoxy” means an —OR′ group where R′ is haloalkyl as definedherein, e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.

“Halogen” or “halo” means fluoro, chloro, bromo and iodo.

“Haloalkyl” means an alkyl group, as defined herein, that is substitutedwith one or more halogens, preferably one to five halo atoms.Representative examples include trifluoromethyl, difluoromethyl,1-chloro-2-fluoro-ethyl, and the like.

“Heteroaryl” means a monocyclic, fused bicyclic, or fused tricyclic,monovalent radical of 5 to 14 ring atoms containing one or more,preferably one, two, three, or four ring heteroatoms independentlyselected from —O—, —S(O)_(n)— (n is 0, 1, or 2), —N—, —N(R^(x))—, andthe remaining ring atoms being carbon, wherein the ring comprising amonocyclic radical is aromatic and wherein at least one of the fusedrings comprising a bicyclic or tricyclic radical is aromatic. One or tworing carbon atoms of any nonaromatic rings comprising a bicyclic ortricyclic radical may be replaced by a —C(O)—, —C(S)—, or —C(═NH)—group. R^(x) is hydrogen, alkyl, hydroxy, alkoxy, acyl, oralkylsulfonyl. Unless stated otherwise, the valency may be located onany atom of any ring of the heteroaryl group, valency rules permitting.In particular, when the point of valency is located on the nitrogen,R^(x) is absent. More specifically, the term heteroaryl includes, but isnot limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl,pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl,2,3-dihydro-1H-indolyl (including, for example,2,3-dihydro-1H-indol-2-yl or 2,3-dihydro-1H-indol-5-yl, and the like),isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl,benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl,phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl,quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl,oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl,isoquinolinyl, tetrahydroisoquinolinyl (including, for example,tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, and the like),pyrrolo[3,2-c]pyridinyl (including, for example,pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, and the like),benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl,benzothienyl, and the derivatives thereof, or N-oxide or a protectedderivative thereof.

“Heteroarylene” means a monocyclic, fused bicyclic, or fused tricyclic,divalent radical of 5 to 14 ring atoms containing one or more,preferably one, two, three, or four ring heteroatoms independentlyselected from —O—, —S(O)_(n)— (n is 0, 1, or 2), —N—, —N(R¹⁹)—, and theremaining ring atoms being carbon, wherein the ring comprising amonocyclic radical is aromatic and wherein at least one of the fusedrings comprising a bicyclic or tricyclic radical is aromatic. One or tworing carbon atoms of any nonaromatic rings comprising a bicyclic ortricyclic radical may be replaced by a —C(O)—, —C(S)—, or —C(═NH)—group. R¹⁹ is hydrogen, alkyl, or alkenyl. Unless stated otherwise, thevalencies may be located on any atom of any ring of the heteroarylenegroup, valency rules permitting. In particular, when the point ofvalency is located on the nitrogen, R^(x) is absent. More specifically,the term heteroaryl includes, but is not limited to, thien-diyl,benzo[d]isoxazol-diyl, benzo[d]isothiazol-diyl, 1H-indazol-diyl(optionally substituted at the N1 position with R¹⁹),benzo[d]oxazol-diyl, benzo[d]thiazol-diyl, 1H-benzo[d]imidazol-diyl(optionally substituted at the N1 position with R¹⁹),1H-benzo[d][1,2,3]triazol-diyl (optionally substituted at the N1position with R¹⁹), imidazo[1,2-a]pyridin-diyl, cinnolin-diyl,quinolin-diyl, pyridin-diyl, 1-oxido-pyridin-diyl,[1,2,4]triazolo[4,3-a]pyridin-diyl, and2,3-dihydroimidazo[1,2-a]pyridin-diyl, and the like.

“Heterocycloalkyl” means a saturated or partially unsaturated (but notaromatic) monovalent monocyclic group of 3 to 8 ring atoms or asaturated or partially unsaturated (but not aromatic) monovalent fusedbicyclic group of 5 to 12 ring atoms in which one or more, specificallyone, two, three, or four ring heteroatoms independently selected from O,S(O)_(n) (n is 0, 1, or 2), N, N(R^(y)) (where R^(y) is hydrogen, alkyl,hydroxy, alkoxy, acyl, or alkylsulfonyl), the remaining ring atoms beingcarbon. One or two ring carbon atoms may be replaced by a —C(O)—,—C(S)—, or —C(═NH)— group. Fused bicyclic radical includes bridged ringsystems. Unless otherwise stated, the valency of the group may belocated on any atom of any ring within the radical, valency rulespermitting. When the point of valency is located on a nitrogen atom,R^(y) is absent. More specifically the term heterocycloalkyl includes,but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl,2,5-dihydro-1H-pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl,piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl,thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl,quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl,decahydroisoquinolyl, tetrahydrofuryl, and tetrahydropyranyl, and thederivatives thereof and N-oxide or a protected derivative thereof.

“Hydroxyalkyl” means an alkyl, as defined herein, substituted with atleast one, preferably one, two, or three, hydroxy group(s), providedthat if two hydroxy groups are present they are not both on the samecarbon atom. Representative examples include, but are not limited to,hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl, and the like.

“Hydroxyamino” means a —NH(OH) group.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. One of ordinary skill in the art would understand that withrespect to any molecule described as containing one or more optionalsubstituents, only sterically practical and/or synthetically feasiblecompounds are meant to be included. “Optionally substituted” refers toall subsequent modifiers in a term. So, for example, in the term“optionally substituted arylC₁₋₈ alkyl,” both the “C₁₋₈ alkyl” portionand the “aryl” portion of the molecule may or may not be substituted. Alist of exemplary optional substitutions is presented below in thedefinition of“substituted.”

“Optionally substituted alkoxy” means an —OR radical where R isoptionally substituted alkyl as defined herein. Representative examplesinclude —OCH₂CH₂OCH₃, —OCH₂CH₂CH₂OH, —OCH₂CH(NH₂)CH₃, and the like.

“Optionally substituted alkyl” means an alkyl radical, as definedherein, optionally substituted with one or more group(s), specificallyone, two, three, four, or five groups, independently selected fromalkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy,alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, cyano,cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, halo, hydroxy,hydroxyalkoxy, carboxy, alkylcarbonylamino, alkylcarbonyloxy,—S(O)₀₋₂-alkyl, —S(O)₀₋₂-alkenyl, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, —NR^(c)S(O)₂-alkyl (where R^(c) is hydrogen,alkyl, optionally substituted alkenyl, optionally substituted alkynyl,hydroxy, alkoxy, alkenyloxy, or cyanoalkyl), alkylaminocarbonyloxy,dialkylaminocarbonyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy,alkoxycarbonyl, alkenyloxycarbonyl, alkoxycarbonylamino,alkylaminocarbonylamino, dialkylaminocarbonylamino, alkoxyalkyloxy, and—C(O)NR^(a)R^(b) (where R^(a) and R^(b) are independently hydrogen,alkyl, optionally substituted alkenyl, optionally substituted alkynyl,hydroxy, alkoxy, alkenyloxy, or cyanoalkyl).

“Optionally substituted aryl” means an aryl group, as defined herein,which is optionally substituted with one, two, three, four, of fivegroups selected from halo, haloalkyl, haloalkoxy, hydroxy, alkyl,alkenyl, alkynyl, alkoxy, carboxy, carboxy ester, amino, alkylamino,dialkylamino, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted heteroaryl, —C(O)NR′R″ (whereR′ is hydrogen or alkyl and R″ is hydrogen, alkyl, aryl, heteroaryl, orheterocycloalkyl), —NR′C(O)R″ (where R′ is hydrogen or alkyl and R″ isalkyl, aryl, heteroaryl, or heterocycloalkyl), and —NHS(O)₂R′ (where R′is alkyl, aryl, or heteroaryl).

“Optionally substituted arylalkyl means an alkyl group substituted withone or two optionally substituted aryl group(s) as defined herein.

“Optionally substituted arylalkyloxy” means an —OR group where R isoptionally substituted arylalkyl, as defined herein.

“Optionally substituted arylalkyloxycarbonyl” means a —C(O)R group whereR is optionally substituted arylalkyloxy, as defined herein.

“Optionally substituted aryloxy” means an —OR group where R isoptionally substituted aryl, as defined herein.

“Optionally substituted aryloxycarbonyl” means a —C(O)R group where R isoptionally substituted aryloxy as defined herein.

“Optionally substituted cycloalkyl” means a cycloalkyl radical, asdefined herein, that is optionally substituted with one, two, three, orfour groups independently selected from alkyl, alkenyl, alkynyl, alkoxy,halo, haloalkyl, haloalkoxy, oxo, hydroxy, cyano, nitro, amino,mono(C₁-C₆)alkylamino, dialkylamino, haloalkyl, haloalkoxy, aminoalkyl,alkylaminoalkyl dialkylaminoalkyl, carboxy, carboxy ester, cycloalkyl,hydroxyalkyl, —C(O)NR′R″ (where R′ is hydrogen, alkyl, hydroxy, oralkoxy and R″ is hydrogen, alkyl, aryl, heteroaryl, orheterocycloalkyl), optionally substituted heterocycloalkyl, optionallysubstituted heteroaryl, —NR′C(O)R″ (where R′ is hydrogen or alkyl and R″is alkyl, aryl, heteroaryl, or heterocycloalkyl), and —NHS(O)₂R′ (whereR′ is alkyl, aryl, or heterocyclyl).

“Optionally substituted cycloalkyloxycarbonyl” means a —C(O)OR groupwhere R is optionally substituted cycloalkyl as defined herein.

“Optionally substituted heteroaryl” means a heteroaryl group, as definedherein, optionally substituted with one, two, three, four, or fivegroups selected from halo, haloalkyl, haloalkoxy, alkyl, alkenyl,alkynyl, alkoxy, hydroxy, oxo (valency rules permitting), carboxy,carboxy ester, amino, alkylamino, dialkylamino, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, heteroaryl,optionally substituted aryl, —C(O)NR′R″ (where R′ is hydrogen or alkyland R″ is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl),—NR′C(O)R″ (where R′ is hydrogen or alkyl and R″ is alkyl, aryl,heteroaryl, or heterocycloalkyl), and —NHS(O)₂R′ (where R′ is alkyl,aryl, or heteroaryl).

“Optionally substituted heterocycloalkyl” means a heterocycloalkyl ring,as defined herein, optionally substituted with one, two, three, four, orfive groups selected from halo, haloalkyl, haloalkoxy, hydroxy, oxo,alkyl, alkenyl, alkynyl, alkoxy, optionally substituted cycloalkyl,heterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, alkoxycarbonyl,aryloxycarbonyl, arylalkyloxycarbonyl, cycloalkyloxycarbonyl,cycloalkylalkyloxycarbonyl, —C(O)NR′R″ (where R′ is hydrogen or alkyland R″ is hydrogen, alkyl, aryl, heteroaryl, or heterocycloalkyl),—NR′C(O)R″ (where R′ is hydrogen or alkyl and R″ is alkyl, aryl,heteroaryl, or heterocycloalkyl), amino, alkylamino, dialkylamino, and—NHS(O)₂R′ (where R′ is alkyl, aryl, or heteroaryl).

“Saturated bridged ring system” refers to a bicyclic or polycyclic ringsystem that is not aromatic. Such a system may contain isolated orconjugated unsaturation, but not aromatic or heteroaromatic rings in itscore structure (but may have aromatic substitution thereon). Forexample, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-1H-indene,7-aza-bicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro-naphthaleneare all included in the class “saturated bridged ring system.”

“Spiro”, “Spirocyclyl” or “spiro ring” refers to a ring originating froma particular annular carbon of another ring. For example, as depictedbelow, a ring atom of a saturated bridged ring system (rings B and B′),but not a bridgehead atom, can be a shared atom between the saturatedbridged ring system and a spirocyclyl (ring A) attached thereto.

“Yield” for each of the reactions described herein is expressed as apercentage of the theoretical yield.

“Patient” for the purposes of the present invention includes humans andother animals, particularly mammals, and other organisms. Thus themethods are applicable to both human therapy and veterinaryapplications. In a specific embodiment the patient is a mammal, and in amore specific embodiment the patient is human.

“Kinase-dependent diseases or conditions” refer to pathologic conditionsthat depend on the activity of one or more protein kinases. Kinaseseither directly or indirectly participate in the signal transductionpathways of a variety of cellular activities including proliferation,adhesion, migration, differentiation and invasion. Diseases associatedwith kinase activities include tumor growth, the pathologicneovascularization that supports solid tumor growth, and associated withother diseases where excessive local vascularization is involved such asocular diseases (diabetic retinopathy, age-related macular degeneration,and the like) and inflammation (psoriasis, rheumatoid arthritis, and thelike).

While not wishing to be bound to theory, phosphatases can also play arole in “kinase-dependent diseases or conditions” as cognates ofkinases; that is, kinases phosphorylate and phosphatasesdephosphorylate, for example protein substrates. Therefore compounds ofthe invention, while modulating kinase activity as described herein, mayalso modulate, either directly or indirectly, phosphatase activity. Thisadditional modulation, if present, may be synergistic (or not) toactivity of compounds of the invention toward a related or otherwiseinterdependent kinase or kinase family. In any case, as statedpreviously, the compounds of the invention are useful for treatingdiseases characterized in part by abnormal levels of cell proliferation(i.e. tumor growth), programmed cell death (apoptosis), cell migrationand invasion and angiogenesis associated with tumor growth.

“Therapeutically effective amount” is an amount of a compound of theinvention, that when administered to a patient, ameliorates a symptom ofthe disease. The amount of a compound of the invention which constitutesa “therapeutically effective amount” will vary depending on thecompound, the disease state and its severity, the age of the patient tobe treated, and the like. The therapeutically effective amount can bedetermined routinely by one of ordinary skill in the art having regardto their knowledge and to this disclosure.

“Cancer” refers to cellular-proliferative disease states, including butnot limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma,Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone:osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, ostcoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis defornians), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic:blood (myeloid leukemia [acute and chronic], acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple mycloma, myelodysplastic syndrome), Hodgkin's disease,non-Hodgkin's lymphoma [malignant lymphoma]; Sin: malignant melanoma,basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;and Adrenal Glands: neuroblastoma. Thus, the term “cancerous cell” asprovided herein, includes a cell afflicted by any one of theabove-identified conditions.

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. It is understood thatthe pharmaceutically acceptable salts are non-toxic. Additionalinformation on suitable pharmaceutically acceptable salts can be foundin Remington's Pharmaceutical Sciences, 17^(th) ed., Mack PublishingCompany, Easton, Pa., 1985, which is incorporated herein by reference orS. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1-19 both of which are incorporated herein by reference.

Examples of pharmaceutically acceptable acid addition salts includethose formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like; as wellas organic acids such as acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonicacid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylicacid and the like.

Examples of a pharmaceutically acceptable base addition salts includethose formed when an acidic proton present in the parent compound isreplaced by a metal ion, such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Preferable salts are the ammonium, potassium, sodium, calcium,and magnesium salts. Salts derived from pharmaceutically acceptableorganic non-toxic bases include, but are not limited to, salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins. Examples of organic bases include isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins,and the like. Exemplary organic bases are isopropylamine, diethylamine,ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

“Prodrug” refers to compounds that are transformed (typically rapidly)in vivo to yield the parent compound of the above formulae, for example,by hydrolysis in blood. Common examples include, but are not limited to,ester and amide forms of a compound having an active form bearing acarboxylic acid moiety. Examples of pharmaceutically acceptable estersof the compounds of this invention include, but are not limited to,alkyl esters (for example with between about one and about six carbons)the alkyl group is a straight or branched chain. Acceptable esters alsoinclude cycloalkyl esters and arylalkyl esters such as, but not limitedto benzyl. Examples of pharmaceutically acceptable amides of thecompounds of this invention include, but are not limited to, primaryamides, and secondary and tertiary alkyl amides (for example withbetween about one and about six carbons). Amides and esters of thecompounds of the present invention may be prepared according toconventional methods. A thorough discussion of prodrugs is provided inT. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

“Metabolite” refers to the break-down or end product of a compound orits salt produced by metabolism or biotransformation in the animal orhuman body; for example, biotransformation to a more polar molecule suchas by oxidation, reduction, or hydrolysis, or to a conjugate (seeGoodman and Gilman, “The Pharmacological Basis of Therapeutics” 8.sup.thEd., Pergamon Press, Gilman et al (eds), 1990 for a discussion ofbiotransformation). As used herein, the metabolite of a compound of theinvention or its salt may be the biologically active form of thecompound in the body. In one example, a prodrug may be used such thatthe biologically active form, a metabolite, is released in vivo. Inanother example, a biologically active metabolite is discoveredserendipitously, that is, no prodrug design per se was undertaken. Anassay for activity of a metabolite of a compound of the presentinvention is known to one of skill in the art in light of the presentdisclosure.

“Treating” or “treatment” of a disease, disorder, or syndrome, as usedherein, includes (i) preventing the disease, disorder, or syndrome fromoccurring in a human, i.e. causing the clinical symptoms of the disease,disorder, or syndrome not to develop in an animal that may be exposed toor predisposed to the disease, disorder, or syndrome but does not yetexperience or display symptoms of the disease, disorder, or syndrome;(ii) inhibiting the disease, disorder, or syndrome, i.e., arresting itsdevelopment; and (iii) relieving the disease, disorder, or syndrome,i.e., causing regression of the disease, disorder, or syndrome. As isknown in the art, adjustments for systemic versus localized delivery,age, body weight, general health, sex, diet, time of administration,drug interaction and the severity of the condition may be necessary, andwill be ascertainable with routine experimentation by one of ordinaryskill in the art.

EMBODIMENTS OF THE INVENTION

In one embodiment of the Invention, R⁷ is halo and all other groups areas defined in the Summary of the Invention for Group A, Group B, GroupC, or Group D. In a more specific embodiment, R⁷ is iodo or bromo. In aneven more specific embodiment, R⁷ is iodo. Yet even more specifically,the compound is that where R⁷ is iodo or bromo and all other groups areas defined in the Summary of the Invention for Group A.

In another embodiment of the Invention, X is halo and all other groupsare as defined in the Summary of the Invention for Group A, Group B,Group C, or Group D. In a more specific embodiment, X is fluoro orchloro. In an even more specific embodiment, X is fluoro. Yet even morespecifically, the compound is that where X is fluoro or chloro and allother groups are as defined in the Summary of the Invention for Group A.

In another embodiment of the Invention, R⁷ and X are halo and all othergroups are as defined in the Summary of the Invention for Group A, GroupB, Group C, or Group D. More specifically, R⁷ is iodo and X is fluoro.Even more specifically, the compound is that where R⁷ is iodo and X isfluoro and all other groups are as defined in the Summary of theInvention for Group A.

In another embodiment of the Invention, R¹, R², R⁵, and R⁶ are hydrogenand all other groups are as defined in the Summary of the Invention forGroup A, Group B, Group C, or Group D. More specifically, R¹, R², R⁵,and R⁶ are hydrogen and all other groups are as defined in the Summaryof the Invention for Group A.

In another embodiment of the Invention, the compound of Formula I isselected from Group A where all groups are as defined in the Summary ofthe Invention.

In another embodiment of the invention (A1), X and R⁷ are halo and allother groups are as defined in the Summary of the Invention for acompound of Group A.

In another embodiment (A2), the compound of Formula I is selected fromGroup A where R¹⁰ and R¹² are independently hydrogen or halo. In a morespecific embodiment, R¹⁰ and R¹² are independently hydrogen or fluoro.More specifically, R¹⁰ is 3-fluoro and R² is hydrogen. In another morespecific embodiment, R¹⁰ and R¹² are fluoro, more specifically, 3-fluoroand 4-fluoro, 4-fluoro and 5-fluoro, or 4-fluoro and 6-fluoro.

In another embodiment of the invention (A3), the compound is that whereR¹, R², R⁵ and R⁶ are hydrogen and all other groups are as defined inthe Summary of the Invention for Group A.

In another embodiment (A4), the compound of Formula I is selected fromGroup A where X, R⁷, and A are as defined in the Summary of theInvention; and

-   one of R¹, R², R³, R⁴, R⁵, and R⁶ is halo, nitro, —NR⁸R^(8′), —OR⁸,    —NHS(O)R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸,    —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″),    —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), —CH₂N(R²⁵)(NR^(25a)R^(25b)),    —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)),    —CH₂NR²⁵C(═NH)(N(R^(25a))(CN)), —CH₂NR²⁵C(═NH)(R²⁵),    —CH₂NR²⁵C(NR^(25a)R^(25b))CH(NO₂), alkyl, alkenyl, alkynyl,    cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl,    alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are    independently optionally substituted with one, two, three, four,    five, six or seven groups independently selected from halo, alkyl,    haloalkyl, nitro, optionally substituted cycloalkyl, optionally    substituted heterocycloalkyl, optionally substituted aryl,    optionally substituted arylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —OR⁸, —NR⁸R^(8′),    —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); and the    others of R¹, R², R³, R⁴, R⁵, and R⁶ are as defined in the Summary    of the Invention; or-   one of R¹ and R² together with the carbon to which they are    attached, R³ and R⁴ together with the carbon to which they are    attached, and R⁵ and R⁶ together with the carbon to which they are    attached forms C(O) or C(═NOH); and the others of R¹, R², R³, R⁴,    R⁵, and R⁶ are as defined in the Summary of the Invention.

In a more another embodiment of the Invention (A5), the compound ofFormula I is selected from Group A where X, R⁷, and A are as defined inthe Summary of the Invention; and

-   R³ is halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸,    —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),    —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),    —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵SC(═NH)(N(R^(25a))(CN)),    —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl,    alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where    the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and    heterocycloalkyl are independently optionally substituted with one,    two, three, four, five, six or seven groups independently selected    from halo, alkyl, haloalkyl, nitro, optionally substituted    cycloalkyl, optionally substituted heterocycloalkyl, optionally    substituted aryl, optionally substituted arylalkyl, optionally    substituted heteroaryl, optionally substituted heteroarylalkyl,    —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸,    —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and    —NR⁸C(O)R^(8′); and R⁴ is as defined in the Summary of the    Invention; or-   R³ and R⁴ together with the carbon to which they are attached form    C(O) or C(═NOH); and-   R¹, R², R⁵ and R⁶ are as defined in the Summary of the invention.

A more specific embodiment of embodiment A5 is that where R¹, R², R⁵ andR⁶ are hydrogen.

In another embodiment of the Invention (A6), the compound of Formula Iis selected from Group A where X, R⁷, and A are as defined in theSummary of the Invention; and

-   R³ and R⁴ are independently halo, nitro, —NR⁸R^(8′), —OR⁸,    —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸,    —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″),    —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), —CH₂N(R²⁵)(NR^(25a)R^(25b)),    —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)),    —CH₂NR²⁵SC(═NH)(N(R^(25a))(CN)), —CH₂NR²⁵C(═NH)(R²⁵),    —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl,    cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl,    alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are    independently optionally substituted with one, two, three, four,    five, six or seven groups independently selected from halo, alkyl,    haloalkyl, nitro, optionally substituted cycloalkyl, optionally    substituted heterocycloalkyl, optionally substituted aryl,    optionally substituted arylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —OR⁸, —NR⁸R^(8′),    —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or-   R³ and R⁴ together with the carbon to which they are attached form    C(O) or C(═NOH);-   R¹, R², R⁵ and R⁶ are are as defined in the Summary of the    Invention.

A more specific embodiment of embodiment A6 is that where R¹, R², R⁵ andR⁶ are hydrogen.

In another embodiment of the Invention (A7), the compound of Formula Iis selected from Group A where X and R⁷ are halo; A is phenyleneoptionally substituted with R¹⁰ and R¹² where R¹⁰ and R¹² areindependently hydrogen or halo; R¹, R², R⁵ and R⁶ are hydrogen;

-   R³ is hydrogen and R⁴ is —NR⁸R^(8′) (where R⁸ is hydrogen, hydroxy,    alkyl, alkoxy, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl and    R^(8′) is hydroxy, alkoxy, aryl, cycloalkyl, heteroaryl, or    heterocycloalkyl), —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′),    —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), alkenyl, and    alkynyl; where the alkenyl and alkynyl are optionally substituted    with one, two, three, four, five, six or seven groups independently    selected from halo, alkyl, haloalkyl, nitro, optionally substituted    cycloalkyl, optionally substituted heterocycloalkyl, optionally    substituted aryl, optionally substituted arylalkyl, optionally    substituted heteroaryl, optionally substituted heteroarylalkyl,    —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸,    —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and    —NR⁸C(O)R^(8′); or-   R³ and R⁴ together with the carbon to which they are attached form    C(O) or C(═NOH);-   m, R^(8″), and R⁹ are as defined in the Summary of the Invention for    a compound of Group A; and unless otherwise specified in this    embodiment, R⁸ and R^(8′) are as defined in the Summary of the    Invention for a compound of Group A.

In another embodiment of the Invention (A8), the compound of Formula Iis selected from Group A where R³ is hydrogen, halo, hydroxy, alkoxy, oramino. More specifically, R³ is hydrogen, fluoro, hydroxy, methoxy, oramino. Even more specifically, R³ is hydrogen or hydroxy. Yet even morespecifically, R³ is hydroxy.

In a more specific embodiment of embodiment A8, X and R⁷ are halo; A isphenylene optionally substituted with R¹⁰ and R¹² where R¹⁰ and R¹² areindependently hydrogen or halo; R¹, R², R⁵ and R⁶ are hydrogen; and R⁴,is as defined in the Summary of the Invention for a compound of Group A.

Another specific embodiment of the Invention (A9) is that where thecompound of Formula I is selected from Group A where R¹, R², R⁵ and R⁶are hydrogen; R³ is hydrogen, halo, hydroxy, alkoxy, or amino; and R⁴ isheterocycloalkyl, heteroaryl, or alkyl substituted with —NR⁸R^(8′) whereR⁸ and R^(8′) and all other groups are as defined in the Summary of theInvention for a compound of Group A.

Another specific embodiment of embodiment A9 is that where R⁴ is alkylsubstituted with —NR⁸R^(8′) where R⁸ and R^(8′) and all other groups areas defined in the Summary of the Invention for a compound of Group A.Specifically, the compound is of Formula I(a) or I(b):

where R³ is as defined in A9; X, R⁷, R⁸, R^(8′), R¹⁰, R¹², R¹⁴, and R¹⁶are as defined in the Summary of the Invention for a compound of GroupA.

Another specific embodiment of embodiment A9 is that where R⁴ isheterocycloalkyl.

In a specific embodiment of embodiment A9, the compound is that where Xand R⁷ are halo; A is phenylene optionally substituted with R¹⁰ and R¹²where R¹⁰ and R¹² are independently hydrogen or halo; R³ is hydroxy; andR⁴ is alkyl substituted with —NR⁸R^(8′) or R⁴ is heterocycloalkyloptionally substituted with one, two, or three groups independentlyselected from halo, alkyl, haloalkyl, nitro, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted arylalkyl, optionallysubstituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″),—NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); and where m, R³, R⁸, R^(8′), R^(8″),and R⁹ are as defined in the Summary of the Invention for a compound ofGroup A.

In another embodiment of the Invention (A10), the compound of Formula Iis selected from Group A where

-   R⁴ is    -   a) hydrogen;    -   b) —CH₂N(R²⁵)(NR^(25a)R^(25b));    -   c) —CH₂NR²⁵SC(NH)(NR²⁵R^(25b));    -   d) —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂));    -   e) —CH₂NR²⁵C(═NH)(N(R^(25a))(CN));    -   f) —CH₂NR²⁵C(═NH)(R²⁵);    -   g) —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂);    -   h) alkyl;    -   i) alkyl substituted with one or two —OR⁸ where R⁸ is hydrogen,        aryl, or alkyl where the alkyl is substituted with one or two        hydroxy;    -   j) alkyl substituted with one, two, or three halo;    -   k) alkyl substituted with nitro;    -   l) alkyl substituted with —S(O)_(m)R⁹ (where m is 0 and R⁹ is        aryl);    -   m) alkyl substituted with optionally substituted        heterocycloalkyl;    -   n) alkenyl;    -   o) —NR⁸R^(8′) (where R⁸ and R^(8′) are independently hydrogen;        alkyl; alkenyl; alkyl substituted with one or two hydroxy; alkyl        substituted with one or two —NR³⁰R^(30′) where R³⁰ and R^(30′)        are independently hydrogen, alkyl, or hydroxyalkyl; alkyl        substituted with optionally substituted heteroaryl; or alkyl        substituted with optionally substituted cycloalkyl);    -   p) —C(O)NR⁸R^(8′) (where R⁸ is hydrogen, alkyl, or alkenyl; and        R^(8′) is hydrogen; hydroxy; alkyl; alkenyl; alkyl substituted        with one or two hydroxy; alkyl substituted with optionally        substituted heterocycloalkyl; alkyl substituted with        —NR³⁰R^(30′) where R³⁰ and R^(30′) are independently hydrogen,        alkyl, or hydroxyalkyl; or optionally substituted alkoxy);    -   q) —NR⁸C(O)OR^(8′) (where R⁸ and R^(8′) are independently        hydrogen, alkyl, or alkenyl);    -   r) alkyl substituted with —NR⁸R^(8′) (where R⁸ is hydrogen,        alkyl, alkenyl, alkynyl, or alkyl substituted with one or two        hydroxy; and R^(8′) is hydrogen; hydroxy; alkoxy; alkyl;        alkenyl; alkynyl; optionally substituted alkoxy; alkyl        substituted with one or two hydroxy; alkyl substituted with one        or two alkoxy; alkyl substituted with —NR³⁰R^(30′) where R³⁰ and        R^(30′) are independently hydrogen, alkyl, or hydroxyalkyl;        alkyl substituted with one or two hydroxy and one or two        —NR³⁰R^(30′) where R³⁰ and R^(30′) are independently hydrogen,        alkyl, or hydroxyalkyl; alkyl substituted with one, two, three,        four, or five halo; alkyl substituted with optionally        substituted cycloalkyl; alkyl substituted with optionally        substituted aryl; alkyl substituted with one or two hydroxy and        one optionally substituted aryl; alkyl substituted with        optionally substituted heterocycloalkyl; alkyl substituted with        optionally substituted heteroaryl; heteroaryl; aryl; aryl        substituted with one or two hydroxy; aryl substituted with one        or two alkoxy; aryl substituted with one or two halo; aryl        substituted with one or two —NR³²C(O)R^(32a) where R³² is        hydrogen or alkyl and R^(32a) is alkyl, alkenyl, alkoxy, or        cycloalkyl; aryl substituted with —NR³⁴SO₂R^(34a) where R³⁴ is        hydrogen or alkyl and R^(34a) is alkyl, alkenyl, cycloalkyl,        aryl, heteroaryl, or heterocycloalkyl; cycloalkyl; cycloalkyl        substituted with one or two hydroxy; cycloalkyl substituted with        one or two hydroxy and one or two hydroxyalkyl; cycloalkyl        substituted with one or two alkoxy; cycloalkyl substituted with        carboxy; cycloalkyl substituted with —C(O)NR³³R^(33a) where R³³        is hydrogen or alkyl and R^(33a) is alkyl, alkenyl, alkynyl, or        cycloalkyl; alkyl substituted with —C(O)NR³³R^(33a) where R³³ is        hydrogen or alkyl and R^(33a) is alkyl, alkenyl, alkynyl, or        cycloalkyl; cycloalkyl substituted with optionally substituted        cycloalkyl; heterocycloalkyl; heterocycloalkyl substituted with        alkyl; heterocycloalkyl substituted with alkoxycarbonyl;        heterocycloalkyl substituted with optionally substituted        arylalkyl; heterocycloalkyl substituted with one or two hydroxy;        heterocycloalkyl substituted with one or two alkoxy;        heterocycloalkyl substituted with one or two hydroxyalkyl;        heterocycloalkyl substituted with one or two hydroxy, one or two        alkoxy, and one or two hydroxyalkyl; alkyl substituted with        optionally substituted aryloxy; alkyl substituted with        —S(O)_(n)R³¹ where n is 0 and R³¹ is alkyl; alkyl substituted        with carboxy; alkyl substituted with alkoxycarbonyl; or alkyl        substituted with —NR³²C(O)R^(32a) where R³² is hydrogen or alkyl        and R^(3i) is alkyl, alkenyl, alkoxy, or cycloalkyl);    -   s) —NR⁸C(O)R^(8′) (where R⁸ is hydrogen, alkyl, or alkenyl; and        R^(8′) is hydrogen; alkyl; alkyl substituted with one or two        hydroxy; alkyl substituted with optionally substituted        heterocycloalkyl; alkyl substituted with —NR³⁰R^(30′) where R³⁰        and R^(30′) are independently hydrogen, alkyl, hydroxyalkyl, or        alkenyl);    -   t) cycloalkyl;    -   u) cycloalkyl substituted with —NR⁸R^(8′) where R⁸ and R^(8′)        are independently hydrogen, alkyl, or alkenyl;    -   v) heterocycloalkyl;    -   w) heterocycloalkyl substituted with —NR⁸R^(8′) where R⁸ and        R^(8′) are independently hydrogen, alkyl, or alkenyl;    -   x) heterocycloalkyl substituted with one or two alkyl;    -   y) heterocycloalkyl substituted with —C(O)OR⁸ where R⁸ is alkyl        or alkenyl;    -   z) alkyl substituted with —NR⁸C(O)R^(8′) (where R⁸ is hydrogen,        alkyl, or alkenyl and R^(8′) is alkyl; alkenyl; or alkyl        substituted with alkoxy, aryl, and one, two, or three halo);    -   aa) heteroaryl;    -   bb) heteroaryl substituted with —NR⁸R^(8′) where R⁸ and R^(8′)        are independently hydrogen, alkyl, or alkenyl; alkyl substituted        with optionally substituted heteroaryl;    -   cc) alkyl substituted with —NR⁸S(O)₂R⁹ where R⁸ is hydrogen,        alkyl, or alkenyl and R⁹ is alkyl or alkenyl;    -   dd) alkyl substituted with —NR⁸C(O)OR^(8′) where R⁸ and R^(8′)        are independently hydrogen, alkyl, or alkenyl;    -   ee) alkyl substituted with one aryl and one —NR⁸R^(8′) where R⁸        and R^(8′) are independently hydrogen, alkyl, or alkenyl; or    -   ff) alkyl substituted with one or two —OR⁸ (where R⁸ is        hydrogen) and one or two —NR⁸R^(8′) where R⁸ and R^(8′) are        independently hydrogen, alkyl, or alkenyl.

Even more specifically, R⁴ is hydrogen, —CH₂N(H)(NHCH₃),—CH₂NHC(═NH)(NH₂), —CH₂NHC(═NH)(NHNO₂), —CH₂NHC(═NH)(NHCN),—CH₂NHC(═NH)(phenyl), —CH₂NHC(NH₂)═CH(NO₂), methyl, ethyl,hydroxymethyl, 2,3-dihydroxypropyl, 3-hydroxy-2-methyl-prop-2-yl,N-(1-methoxy-prop-2-yl)-aminomethyl, N-(ethoxypropyl)-aminomethyl,N-(ethoxyethyl)-aminomethyl, N-(2,2-dimethoxyethyl)-aminomethyl,N-(methoxyethyl)-aminomethyl, N-(isopropxyethyl)-aminomethyl,trifluoromethyl, 1-nitro-ethyl, 1-methyl-1-nitro-ethyl, 1-nitro-propyl,3-methyl-1-nitro-butyl, phenylthiomethyl, allyl, ethenyl,2-methylthio-ethylaminomethyl, 3-methylthio-propylaminomethyl,N-(tert-butoxycarbonylaminopropyl)-aminomethyl,N-(1-carboxyethyl)-aminomethyl, N-(1R-carboxyethyl)-aminomethyl,N-(1S-carboxyethyl)-aminomethyl, N-(1-methoxycarbonylethyl)-aminomethyl,—NH₂, —NH(CH₂)₃CH₃, —NHCH₃, —NH(CH₂CH₃), —NHCH₂CH(CH₃)₂, —NHCH₂CH₂OH,—NHCH₂CH₂CH₂NH₂, —N(CH₃)CH₂CH₂(heteroaryl), —NHCH₂(cycloalkyl),—C(O)NH₂, —C(O)NHOH, —C(O)NH(OCH₂CH(OH)CH₂OH), —C(O)NH(CH₂)₃CH₃,—C(O)NHCH₂CH═CH₂, —C(O)NHCH₂CH₃, —C(O)NHCH₂CH₂OH,—C(O)NHCH₂CH—(OH)CH₂OH, —C(O)NHCH₂CH₂CH(OH)CH₂OH),—C(O)NHCH₂CH₂(piperidin-1-yl), —C(O)NH(phenyl), —C(O)NHCH₂CH₂N(CH₂CH₃)₂,—NHC(O)OC(CH₃)₃, —NHC(O)OCH₃, azetidinylmethyl, pyrrolidinylmethyl,3-hydroxy-pyrrolidinylmethyl, 2-(methoxymethyl)-pyrrolidinylmethyl,2S-(methoxymethyl)-pyrrolidinylmethyl,2R-(methoxymethyl)-pyrrolidinylmethyl, morpholinylmethyl,hydroxypiperidinylmethyl, 4-alkyl-piperazinylmethyl,4-alkyl-homopiperazinylmethyl, 4-(heterocycloalkyl)-piperidinylmethyl,4-(dialkylaminoalkyl)-piperazinylmethyl, N-hydroxyaminoethyl,N-methoxyaminomethyl, N-ethoxyaminoethyl, N-ethylaminomethyl,1-(N-ethyl-amino)-ethyl, N,N-diethylaminomethyl,N,N-dimethylaminomethyl, aminomethyl, 1-amino-ethyl, 1R-amino-ethyl,1S-amino-ethyl, 1_(methylamino)-ethyl, 1-(N,N-dimethylamino)-ethyl,1-amino-1-methyl-ethyl, 1-aminopropyl, 1S-aminopropyl, 1R-aminopropyl,N-(n-propyl)-aminomethyl, N-(isopropyl)-aminomethyl,2-(N-isopropylamino)-ethyl, 3-(N-isopropylamino)-2-methyl-prop-2-yl,1-(N-ethyl-amino)-propyl, 1-(N,N-diethyl-amino)-propyl, 1-iminobutyl,1-amino-isobutyl, N-(2-aminoethyl)-aminomethyl, N-(n-butyl)-aminomethyl,N-isobutylaminomethyl, tert-butylaminomethyl, 1-(tert-butylamino)-ethyl,sec-butylaminomethyl, N-(2-methyl-but-3-yl)-aminomethyl,N-(3,3-dimethyl-butyl)-aminomethyl, N-(3-methylbut-3-yl)-aminomethyl,N-(2-methylbutyl)-aminomethyl, N-(pent-3-yl)-aminomethyl,n-pentylaminoethyl, isopentylaminomethyl, sec-pentylaminoethyl,neopentylaminoethyl, N-(2,2,4-trimethyl-pent-4-yl)-aminomethyl,N-(2-ethyl-butyl)-aminomethyl, N-allyl-aminomethyl,3-methyl-but-1-yn-3-ylaminomethyl,N-(2,3-dihydroxypropyloxy)-aminomethyl, N-cyclopropylaminomethyl,N-cyclobutylaminomethyl, N-cyclopentylaminomethyl,N-cyclopenten-4-ylaminomethyl,N-(1(R,S)-hydroxy-cyclopent-2-yl)-aminomethyl, N-(1S-hydroxy-cyclopent-2-yl)-aminomethyl,N-(1R-hydroxy-cyclopent-2-yl)-aminomethyl,N-(1(R,S)-hydroxy-1-methyl-cyclopent-2-yl)-aminomethyl,N-(1S-hydroxy-1-methyl-cyclopent-2-yl)-aminomethyl,N-(1R-hydroxy-1-methyl-cyclopent-2-yl)-aminomethyl,N-(3,4-dihydroxy-cyclopentyl)-aminomethyl,N-(1-hydroxymethyl-cyclopent-1-yl)-aminomethyl,N-(2,3-dihydroxy-4-hydroxymethyl-cyclopentyl)-aminomethyl,N-(1(R,S)-methoxy-cyclopent-2-yl)-aminomethyl,N-(1S-methoxy-cyclopent-2-yl)-aminomethyl,N-(1R-methoxy-cyclopent-2-yl)-aminomethyl,N-(1-carboxy-cyclopentyl)-aminomethyl, N-cyclohexylaminomethyl,N-(1(R,S)-hydroxy-cyclohex-2-yl)-aminomethyl,N-(cis-4-hydroxy-cyclohexyl)-aminomethyl,N-(trans-4-hydroxy-cyclohexyl)-aminomethyl,1-[N-(cis-4-hydroxy-cyclohexyl)-amino]-ethyl,1-[N-(trans-4-hydroxy-cyclohexyl)-amino]-ethyl,N-(1(R)-hydroxy-cyclohex-2-yl)-aminomethyl,N-(1S)-hydroxy-cyclohex-2-yl)-aminomethyl,N-(1-hydroxymethyl-cyclohexyl)-aminomethyl,N-(2-cyclohexyl-cyclohexyl)-aminomethyl,N-{(2R,3S,4R,6R)-2-(hydroxymethyl)-3,4-dihydroxy-6-methoxy-tetrahydro-2H-pyran-5-yl}-aminomethyl,N-(cycloheptyl)-aminomethyl, N-(cyclooctyl)-aminomethyl,[(1r,3r,5R,7R)-tricyclo[3.3.1.1˜3,7˜]dec-2-ylamino]methyl,N-[1-(cyclopropylaminocarbonyl)-cyclopenyl]-aminomethyl,—CH₂NHC(CH₃)₂C(O)NH(cyclohexyl), —CH₂NHC(CH₃)₂C(O)NH(CH₂CH₃),N-(1-benzyloxy-cyclopent-2-yl)-aminomethyl,N-(cyclopropylmethyl)-aminomethyl, N-(cyclohexylmethyl)-aminomethyl,N-(1-cyclohexylethyl)-aminomethyl, N-(imidazolyl)-aminomethyl,N-(1,3,5-triazinyl)-aminomethyl, N-(5-hydroxy-pyrazol-3-yl)-aminomethyl,N-(5-methyl-pyrazol-3-yl)-aminomethyl, N-(benzimidazolyl)-aminomethyl,N-(pyrimidin-2-yl)-aminomethyl, N-(pyridin-2-yl)-aminomethyl,N-(pyridin-3-yl)-aminomethyl, N-(pyridin-4-yl)-aminomethyl, Nindan-1-yl-aminomethyl, N-indan-2-yl-aminomethyl, phenylaminomethyl,N-(2-hydroxyphenyl)-aminomethyl, N-(3-hydroxyphenyl)-aminomethyl,N-(4-hydroxyphenyl)-aminomethyl, N-(2-methoxyphenyl)-aminomethyl,N-(3-methoxyphenyl)-aminomethyl, N-(4-methoxyphenyl)-aminomethyl,N-(2-fluorophenyl)-aminomethyl, N-(3-fluorophenyl)-aminomethyl,N-(4-fluorophenyl)-aminomethyl, N-(2-chlorophenyl)-aminomethyl,N-(3-chlorophenyl)-aminomethyl, N-(4-chlorophenyl)-aminomethyl,N-(3-methylcarbonylamino-phenyl)-aminomethyl,N-(4-methylcarbonylamino-phenyl)-aminomethyl,N-(2-aminophenyl)-aminomethyl, N-(3-aminophenyl)-amino methyl,N-(4-aminophenyl)-aminomethyl,N-(2-methylsulfonylaminophenyl)-aminomethyl,N-(3-methylsulfonylaminophenyl)-aminomethyl,N-(4-methylsulfonylaminophenyl)-aminomethyl,N-(2-fluoro-4-hydroxy-phenyl)-aminomethyl,N-(3-fluoro-4-hydroxy-phenyl)-aminomethyl, N-(benzyl)-aminomethyl,N-(2-hydroxyphenylmethyl)-aminomethyl,N-(3-hydroxyphenylmethyl)-aminomethyl,N-(4-hydroxyphenylmethyl)-aminomethyl,N-(2-N-methylpiperazin-1-yl)-phenylmethyl)-aminomethyl,N-(4-alkyl-phenethyl)-aminomethyl,N-(1-hydroxy-3-phenyl-prop-2-yl)-aminomethyl,N-(pyrrolidin-2-ylmethyl)-aminomethyl,N-(N-alkyl-pyrrolidinylmethyl)-aminomethyl,N-(N-alkyl-pyrrolidinylethyl)-aminomethyl,N-(pyrrolidinylpropyl)-aminomethyl,N-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-aminomethyl,N-(tetrahydrofuranylmethyl)-aminomethyl,N-(tetrahydro-2H-pyran-4-ylmethyl)-aminomethyl,N-(tetrahydro-2H-pyranylethyl)-aminomethyl,N-(piperidin-4-ylmethyl)-aminomethyl,N-(N-methylpiperidin-4-ylmethyl)-aminomethyl,N-(N-tert-butoxycarbonylpiperidin-4-ylmethyl)-aminomethyl,N-(N-methylimidazol-4-ylmethyl)-aminomethyl,N-(N-methylimidazol-5-ylmethyl)-aminomethyl,N-[2-(imidazol-4-yl)-ethyl]-aminomethyl,N-[3-(imidazolyl)-propyl]-aminomethyl,N-(pyridin-3-ylethyl)-aminomethyl, N-(pyridin-4-ylethyl)-aminomethyl,N-(thien-2-ylethyl)-aminomethyl, N-(furan-2-ylethyl)-aminomethyl,N-(5-methyl-1,3,4-oxadiazol-2-ylmethyl)-aminomethyl,N-(2-indolin-3-ylethyl)-aminomethyl,2-(N,N-dimethylamino)-ethylaminomethyl,2-(N,N-dimethylamino)-1-methyl-ethylaminomethyl,3-aminopropylaminoethyl, 3-(N,N-dimethylamino)-propylaminomethyl,3-(N,N-diethylamino)-propylaminomethyl,N-(N,N-diisopropylaminoethyl)-aminomethyl,N-(N,N-dimethylaminobutyl)-aminomethyl, N-(3-hydroxypropyl)-aminomethyl,N-(2-hydroxypropyl)-aminomethyl, N-(1,2-dihydroxypropyl)-aminomethyl,N-(1-amino-2-hydroxy-prop-3-yl)-aminomethyl,N-(N-ethoxycarbonyl-piperidin-4-yl)-aminomethyl,N-(N-benzylpiperidin-4-yl)-aminomethyl,N-(homopiperidin-3-yl)-aminomethyl,N-(N-benzylpyrrolidin-3-yl)-aminomethyl,N-(N-ethylpiperidin-3-yl)aminomethyl, 2,2,2-trifluoroethylaminomethyl,3,3,3-trifluoropropylaminomethyl,2,2,3,3,3-pentafluoropropylaminomethyl, —CH₂N(CH₂CH₂OH),—CH₂N(CH₃)(CH₂CH₂OH), —CH₂NH(CH₂CH₂OH), —CH₂NH(CH₂CH₂CH₂CH₂OH),—CH₂N(CH₃)(N-methyl-pyrrolidin-3-yl), —CH₂NH(C(CH₃)₂CH₂OH),—NHC(O)CH(CH₃)₂, —NHC(O)CH₂N(CH₂CH₃)₂, —NHC(O)CH₂NH(CH₃), —NHC(O)H,—NHC(O)CH₂CH(OH)CH₂OH, —NHC(O)CH₂NH₂, —NHC(O)CH₂N(CH₂CH₂OH)₂,—NHC(O)CH₂CH₂N(CH₂CH₂OH)₂, —NHC(O)CH₂(4-alkyl-piperazinyl),—NHC(O)CH₂(piperidinyl), N-(phenyloxyethyl)-aminomethyl, cyclopentyl,1-amino-cyclopentyl, (cis,trans)-2-amino-cyclopentyl,(cis,tran)-2-amino-cyclopentyl, cis-2-amino-cyclopentyl,trans-2-amino-cyclopentyl, (cis,trans)-2-hydroxy-cyclohexyl,cis-2-hydroxy-cyclohexyl, trans-2-hydroxy-cyclohexyl,(cis,trans)-2-amino-cyclohexyl, cis-2-amino-cyclohexyl,trans-2-amino-cyclohexyl, azetidin-3-yl, pyrrolidinyl,N-alkyl-pyrrolidinyl, 3-(dialkylamino)-pyrrolidinyl, piperidinyl,2-methyl-piperidin-6-yl, N-tert-butoxycarbonylpiperidin-2-yl,piperazinyl, —CH₂NHC(O)CH₃, —CH(CH₃)NHC(O)CH₃,—CH(CH₃)NHC(O)C(OCH₃)(CF₃)phenyl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl,imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl,N-methyl-imidazol-2-yl, 5-methyl-imidazol-2-yl, 1,2,4-triazol-3-yl,thiazol-2-yl, 2-aminopyrimidin-3-yl, pyridinyl, benzimidazolyl,imidazol-1-ylmethyl, imidazol-2-ylmethyl, triazolylmethyl,(5-amino-3-methylpyrazol-1-yl)-methyl, phenoxymethyl,methylsulfonylaminomethyl, 1-(methoxycarbonylamino)-ethyl,1-amino-1-phenyl-methyl, or 1-amino-3-hydroxy-propyl.

A more specific embodiment of embodiment A10 is that wherein X and R⁷are halo; A is phenylene optionally substituted with R¹⁰ and R¹² whereR¹⁰ and R¹² are independently hydrogen or halo; R¹, R², R⁵ and R⁶ arehydrogen; and R³ is hydrogen, halo, hydroxy, alkoxy, or amino.

A more specific embodiment of embodiment A10 is that where R is hydrogenand R⁴ is

-   -   a) hydrogen;    -   b) —NR⁸R^(8′) (where R⁸ and R^(8′) are independently hydrogen;        alkyl; alkenyl; alkyl substituted with one or two hydroxy; alkyl        substituted with one or two —NR³⁰R^(30′) where R³⁰ and R^(30′)        are independently hydrogen, alkyl, or hydroxyalkyl; alkyl        substituted with optionally substituted heteroaryl; or alkyl        substituted with optionally substituted cycloalkyl);    -   c) —C(O)NR′R^(8′) (where R⁸ is hydrogen, alkyl, or alkenyl; and        R^(8′) is hydrogen; hydroxy; alkyl; alkenyl; alkyl substituted        with one or two hydroxy; alkyl substituted with        heterocycloalkyl; alkyl substituted with —NR³⁰R^(30′) where R³⁰        and R^(30′) are independently hydrogen, alkyl, or hydroxyalkyl;        or optionally substituted alkoxy);    -   d) —NR⁸C(O)OR^(8′) (where R⁸ and R^(8′) are independently        hydrogen, alkyl, or alkenyl);    -   e) —NR⁸C(O)R^(8′) (where R⁸ is hydrogen, alkyl, or alkenyl; and        R^(8′) is hydrogen; alkyl; alkyl substituted with one or two        hydroxy; alkyl substituted with optionally substituted        heterocycloalkyl; alkyl substituted with —NR³⁰R^(30′) where R³⁰        and R^(30′) are independently hydrogen, alkyl, hydroxyalkyl, or        alkenyl);    -   f) alkyl;    -   g) alkyl substituted with one or two —OR⁸ (where R⁸ is        hydrogen);    -   h) alkyl substituted with —NR⁸R^(8′) (where R⁸ is hydrogen,        alkyl, alkenyl, alkynyl, or alkyl substituted with one or two        hydroxy; and R^(8′) is hydrogen; alkyl; alkenyl; alkynyl; alkyl        substituted with one or two hydroxy; heterocycloalkyl        substituted with alkyl; or alkyl substituted with —NR³⁰R^(30′)        where R³⁰ and R^(30′) are independently hydrogen, alkyl, or        hydroxyalkyl);    -   i) heterocycloalkyl; or    -   j) heterocycloalkyl substituted with —NR⁸R^(8′) (where R⁸ and        R^(8′) are independently hydrogen, alkyl, or alkenyl).

Even more specifically, R³ is hydrogen and R⁴ is hydrogen,hydroxymethyl, —NH₂, —NH(CH₂)₃CH₃, —NHCH₃, —NH(CH₂CH₃), —NHCH₂CH(CH₃)₂,—NHCH₂CH₂OH, —NHCH₂CH₂CH₂NH₂, —N(CH₃)CH₂CH₂(pyridin-2-yl),—NHCH₂(cyclopropyl), —NHCH₂(cyclopentyl), —NHCH₂(cyclohexyl), —C(O)NHOH,—C(O)NH(OCH₂CH(OH)CH₂OH), —C(O)NH(CH₂)₃CH₃, —C(O)NHCH₂CH═CH₂,—C(O)NHCH₂CH₃, —C(O)NHCH₂CH₂OH, —C(O)NHCH₂CH(OH)CH₂OH,—C(O)NHCH₂CH₂CH(OH)CH₂OH, —C(O)NHCH₂CH₂(piperidin-1-yl),—C(O)NH(phenyl), —C(O)NHCH₂CH₂N(CH₂CH₃)₂, N-(isopropyl)-aminomethyl,N,N-dimethylaminomethyl, N-(2-aminoethyl)-aminomethyl, —NHC(O)OC(CH₃)₃,—NHC(O)OCH₃, —NHC(O)CH(CH₃)₂, —NHC(O)CH₂NH₂, —NHC(O)CH₂N(CH₂CH₃)₂,—NHC(O)CH₂NH(CH₃), —NHC(O)H, —NHC(O)CH₂CH(OH)CH₂OH,—NHC(O)CH₂N(CH₂CH₂OH)₂, —NHC(O)CH₂CH₂N(CH₂CH₂OH)₂,—NHC(O)CH₂(4-alkyl-piperazinyl), —NHC(O)CH₂(piperidinyl), pyrrolidinyl,3-(dialkylamino)-pyrrolidinyl, piperidinyl, 2-methyl-piperidin-6-yl,N-methylpiperidin-2-yl, or piperazin-2-yl.

A more specific embodiment of embodiment A10 is that where R³ is alkoxyand R⁴ is alkyl substituted with —NR⁸R^(8′) (where R⁸ and R^(8′) areindependently hydrogen, alkyl, or alkenyl). More specifically, R³ ismethoxy and R⁴ is alkyl substituted with —NR⁸R^(8′) (where R⁸ and R^(8′)are independently hydrogen, alkyl, or alkenyl).

A more specific embodiment of embodiment A10 is that where R³ is haloand R⁴ is alkyl substituted with —NR⁸R^(8′) (where R⁸ and R^(8′) areindependently hydrogen, alkyl, or alkenyl). More specifically, R³ isfluoro and R⁴ is alkyl substituted with —NR⁸R^(8′) (where R⁸ and R^(8′)are independently hydrogen, alkyl, or alkenyl).

A more specific embodiment of embodiment A10 is that where R³ is aminoand R⁴ is alkyl substituted with —NR⁸R^(8′) (where R⁸ and R^(8′) areindependently hydrogen, alkyl, or alkenyl).

A more specific embodiment of embodiment A10 is that where R³ is hydroxyand R⁴ is

-   -   a) hydrogen;    -   b) —CH₂N(R²⁵)(NR^(25a)R^(25b));    -   c) —CH₂NR²⁵SC(NH)(NR²⁵R^(25b));    -   d) —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂));    -   e) —CH₂NR²⁵C(═NH)(N(R^(25a))(CN));    -   f) —CH₂NR²⁵C(═NH)(R²⁵);    -   g) —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂);    -   h) alkyl;    -   i) alkenyl;    -   j) alkyl substituted with one or two —OR⁸ where R⁸ is hydrogen,        aryl, or alkyl where the alkyl is substituted with one or two        hydroxy;    -   k) alkyl substituted with one, two, or three halo;    -   l) alkyl substituted with nitro;    -   m) alkyl substituted with —S(O)_(m)R⁹ (where m is 0 and R⁹ is        aryl);    -   n) alkyl substituted with optionally substituted        heterocycloalkyl;    -   o) alkyl substituted with —NR⁸R^(8′) (where R⁸ is hydrogen,        alkyl, alkenyl, alkynyl, or alkyl substituted with one or two        hydroxy; and R^(8′) is hydrogen; hydroxy; alkoxy; alkyl;        alkenyl; alkynyl; optionally substituted alkoxy; alkyl        substituted with one or two hydroxy; alkyl substituted with        —NR³⁰R^(30′) where R³⁰ and R^(30′) are independently hydrogen,        alkyl, or hydroxyalkyl; alkyl substituted with one or two        hydroxy and one or two —NR³⁰R^(30′) where R³⁰ and R^(30′) are        independently hydrogen, alkyl, or hydroxyalkyl; heterocycloalkyl        substituted with alkyl, alkoxycarbonyl, or optionally        substituted arylalkyl; alkyl substituted with one, two, three,        four, or five halo; alkyl substituted with optionally        substituted cycloalkyl; alkyl substituted with optionally        substituted aryl; alkyl substituted with one or two hydroxy and        one optionally substituted aryl; alkyl substituted with        optionally substituted heterocycloalkyl; alkyl substituted with        optionally substituted heteroaryl; heteroaryl; aryl; aryl        substituted with one or two hydroxy; aryl substituted with one        or two alkoxy; aryl substituted with one or two halo; aryl        substituted with one or two —NR³²C(O)R^(32a) where R³² is        hydrogen or alkyl and R^(32a) is alkyl, alkenyl, alkoxy, or        cycloalkyl; aryl substituted with —NR³⁴SO₂R³⁴ where R³⁴ is        hydrogen or alkyl and R^(34a) is alkyl, alkenyl, cycloalkyl,        aryl, heteroaryl, or heterocycloalkyl; cycloalkyl; cycloalkyl        substituted with one or two hydroxy; cycloalkyl substituted with        one or two hydroxy and one or two hydroxyalkyl; cycloalkyl        substituted with one or two alkoxy; cycloalkyl substituted with        carboxy; cycloalkyl substituted with —C(O)NR³³R^(33a) where R³³        is hydrogen or alkyl and R^(33a) is alkyl, alkenyl, alkynyl, or        cycloalkyl; cycloalkyl substituted with optionally substituted        cycloalkyl; heterocycloalkyl; heterocycloalkyl substituted with        one or two hydroxy; heterocycloalkyl substituted with one or two        alkoxy; heterocycloalkyl substituted with one or two        hydroxyalkyl; heterocycloalkyl substituted with one or two        hydroxy, one or two alkoxy, and one or two hydroxyalkyl; alkyl        substituted with —C(O)NR³³R^(33a) where R³³ is hydrogen or alkyl        and R^(33a) is alkyl, alkenyl, alkynyl, or cycloalkyl; alkyl        substituted with optionally substituted aryloxy; alkyl        substituted with —S(O)_(n)R³¹ where n is 0 and R³¹ is alkyl;        alkyl substituted with carboxy; alkyl substituted with        alkoxycarbonyl; or alkyl substituted with —NR³²C(O)R^(32a) where        R³² is hydrogen or alkyl and R^(32a) is alkyl, alkenyl, alkoxy,        or cycloalkyl);    -   p) heterocycloalkyl;    -   q) —C(O)NR⁸R^(8′) (where R⁸ is hydrogen, alkyl, or alkenyl; and        R^(8′) is hydrogen; alkyl; alkyl; alkenyl; or substituted with        one or two hydroxy);    -   r) alkyl substituted with —NR⁸C(O)R^(8′) (where R⁸ is hydrogen,        alkyl, or alkenyl and R^(8′) is alkyl; alkenyl; or alkyl        substituted with alkoxy, aryl, and one, two, or three halo);    -   s) cycloalkyl;    -   t) cycloalkyl substituted with —NR⁸R^(8′) where R⁸ and R^(8′)        are independently hydrogen, alkyl, or alkenyl;    -   u) cycloalkyl substituted with —C(O)NR³³R^(33a) where R³³ is        hydrogen or alkyl and R^(33a) is alkyl, alkenyl, alkynyl, or        cycloalkyl;    -   v) heterocycloalkyl;    -   w) heterocycloalkyl substituted with one or two alkyl;    -   x) heterocycloalkyl substituted with —C(O)OR⁸ where R^(8′) is        alkyl or alkenyl;    -   y) heteroaryl;    -   z) heteroaryl optionally substituted with —NR⁸R^(8′) where R⁸        and R^(8′) are independently hydrogen, alkyl, or alkenyl;    -   aa) alkyl substituted with optionally substituted heteroaryl;    -   bb) alkyl substituted with —NR⁸S(O)₂R⁹ where R⁸ is hydrogen,        alkyl, or alkenyl and R⁹ is alkyl or alkenyl;    -   cc) alkyl substituted with —NR⁸C(O)OR where R¹ and R^(8′) are        independently hydrogen, alkyl, or alkenyl;    -   dd) alkyl substituted with one aryl and one —NR⁸R^(8′) where R⁸        and R^(8′) are independently hydrogen, alkyl, or alkenyl; or    -   cc) alkyl substituted with one or two —OR⁸ (where R⁸ is        hydrogen) and one or two —NR⁸R^(8′) where R⁸ and R^(8′) are        independently hydrogen, alkyl, or alkenyl.

Even more specifically, R³ is hydroxy and R⁴ is hydrogen,—CH₂N(H)(NHCH₃), —CH₂NHC(═NH)(NH₂), —CH₂NHC(═NH)(NHNO₂),—CH₂NHC(═NH)(NHCN), —CH₂NHC(═NH)(phenyl), —CH₂NHC(NH₂)═CH(NO₂), methyl,ethyl, hydroxymethyl, 2,3-dihydroxypropyl, 3-hydroxy-2-methyl-prop-2-yl,N-(1-methoxy-prop-2-yl)-aminomethyl, N-(ethoxypropyl)-aminomethyl,N-(ethoxyethyl)-aminomethyl, N-(2,2-dimethoxyethyl)-aminomethyl,N-(methoxyethyl)-aminomethyl, N-(isopropxyethyl)-aminomethyl,trifluoromethyl, 1-nitro-ethyl, 1-methyl-1-nitro-ethyl, 1-nitro-propyl,3-methyl-1-nitro-butyl, phenylthiomethyl, allyl, ethenyl,2-methylthio-ethylaminomethyl, 3-methylthio-propylaminomethyl,N-(tert-butoxycarbonylaminopropyl)-aminomethyl,N-(1-carboxyethyl)-aminomethyl, N-(1R-carboxyethyl)-aminomethyl,N-(1S-carboxyethyl)-aminomethyl, N-(1-methoxycarbonylethyl)-aminomethyl,azetidinylmethyl, pyrrolidinylmethyl, 3-hydroxy-pyrrolidinylmethyl,2-(methoxymethyl)-pyrrolidinylmethyl,2S-(methoxymethyl)-pyrrolidinylmethyl,2R-(methoxymethyl)-pyrrolidinylmethyl, morpholinylmethyl,4-hydroxypiperidinylmethyl, 4-methyl-piperazinylmethyl,4-methyl-homopiperazinylmethyl, 4-(piperidinyl)-piperidinylmethyl,4-[2-(N, N-diethylamino)-ethyl]-piperazinylmethyl, N-hydroxyaminoethyl,N-methoxyaminomethyl, N-ethoxyaminoethyl, N-ethylaminomethyl,1-(N,N-ethyl-amino)-ethyl, N,N-diethylaminomethyl,N,N-dimethylaminomethyl, aminomethyl, 1-amino-ethyl, 1R-amino-ethyl,IS-amino-ethyl, 1-(methylamino)-ethyl, 1-(N,N-dimethylamino)-ethyl,1-amino-1-methyl-ethyl, 1-aminopropyl, 1S-aminopropyl, 1R-aminopropyl,N-(n-propyl)-aminomethyl, N-(isopropyl)-aminomethyl,2-(N-isopropylamino)-ethyl, 3-(N-isopropylamino)-2-methyl-prop-2-yl,1-(N-ethyl-amino)-propyl, 1-(N,N-diethyl-amino)-propyl, 1-aminobutyl,1-amino-isobutyl, N-(n-butyl)-aminomethyl, N-isobutylaminomethyl,tert-butylaminomethyl, 1-(tert-butylamino)-ethyl, sec-butylaminomethyl,N-(2-methyl-but-3-yl)-aminomethyl, N-(3,3-dimethyl-butyl)-aminomethyl,N-(3-methylbut-3-yl)-aminomethyl, N-(2-methylbutyl)-aminomethyl,N-(pent-3-yl)-aminomethyl, n-pentylaminoethyl, isopentylaminomethyl,sec-pentylaminomethyl, neopentylaminomethyl,N-(2,2,4-trimethyl-pent-4-yl)-aminomethyl,N-(2-ethyl-butyl)-aminomethyl, N-allyl-aminomethyl,3-methyl-but-1-yn-3-ylaminomethyl,N-(2,3-dihydroxypropyloxy)-aminomethyl, N-cyclopropylaminomethyl,N-cyclopentylaminomethyl, N-cyclopenten-4-ylaminomethyl,N-(1(R,S)-hydroxy-cyclopent-2-yl)-aminomethyl,N-(1S-hydroxy-cyclopent-2-yl)-aminomethyl,N-(1R-hydroxy-cyclopent-2-yl)-aminomethyl,N-(1(R,S)-hydroxy-1-methyl-cyclopent-2-yl)-aminomethyl,N-(1S-hydroxy-1-methyl-cyclopent-2-yl)-aminomethyl,N-(1R-hydroxy-1-methyl-cyclopent-2-yl)-aminomethyl,N-(3,4-dihydroxy-cyclopentyl)-aminomethyl,N-(1-hydroxymethyl-cyclopent-1-yl)-aminomethyl,N-(2,3-dihydroxy-4-hydroxymethyl-cyclopentyl)-aminomethyl,N-(1(R,S)-methoxy-cyclopent-2-yl)-aminomethyl,N-(1S-methoxy-cyclopent-2-yl)-aminomethyl,N-(1R-methoxy-cyclopent-2-yl)-aminomethyl,N-(1-carboxy-cyclopentyl)-aminomethyl, N-cyclohexylaminomethyl,N-(1(R,S)-hydroxy-cyclohex-2-yl)-aminomethyl,N-(1(R)-hydroxy-cyclohex-2-yl)-aminomethyl,N-(1(S)-hydroxy-cyclohex-2-yl)-aminomethyl,N-(cis-4-hydroxy-cyclohexyl)-aminomethyl,N-(trans-4-hydroxy-cyclohexyl)-aminomethyl,1-[N-(cis-4-hydroxy-cyclohexyl)-amino]-ethyl,1-[N-(trans-4-hydroxy-cyclohexyl)-amino]-ethyl,N-(1-hydroxymethyl-cyclohexyl)-aminomethyl,N-(2-cyclohexyl-cyclohexyl)-aminomethyl,N-{(2R,3S,4R,6R)-2-(hydroxymethyl)-3,4-dihydroxy-6-methoxy-tetrahydro-2H-pyran-5-yl}-aminomethyl,N-(cycloheptyl)-aminomethyl, N-(cyclooctyl)-aminomethyl,[(1r,3r,5R,7R)-tricyclo[3.3.1.1˜3,7˜]dec-2-ylamino]methyl,N-(1-benzyloxy-cyclopent-2-yl)-aminomethyl,N-[1-(cyclopropylaminocarbonyl)-cyclopentyl]-aminomethyl,—CH₂NHC(CH₃)₂C(O)NH(cyclohexyl), —CH₂NHC(CH₃)₂C(O)NH(CH₂CH₃),N-(cyclopropylmethyl)-aminomethyl, N-(cyclohexylmethyl)-aminomethyl,N-(1-cyclohexylethyl)-aminomethyl, N-(imidazolyl)-aminomethyl,N-(1,3,5-triazinyl)-aminomethyl, N-(5-hydroxy-pyrazol-3-yl)-aminomethyl,N-(5-methyl-pyrazol-3-yl)-aminomethyl, N-(benzimidazolyl)-aminomethyl,N-(pyrimidin-2-yl)-aminomethyl, N-(pyridin-2-yl)-aminomethyl,N-(pyridin-3-yl)-aminomethyl, N-(pyridin-4-yl)-aminomethyl,N-indan-1-yl-aminomethyl, N-indan-2-yl-aminomethyl, phenylaminomethyl,N-(2-hydroxyphenyl)-aminomethyl, N-(3-hydroxyphenyl)-aminomethyl,N-(4-hydroxyphenyl)-aminomethyl, N-(2-methoxyphenyl)-aminomethyl,N-(3-methoxyphenyl)-aminomethyl, N-(4-methoxyphenyl)-aminomethyl,N-(2-fluorophenyl)-aminomethyl, N-(3-fluorophenyl)-aminomethyl,N-(4-fluorophenyl)-aminomethyl, N-(2-chlorophenyl)-aminomethyl,N-(3-chlorophenyl)-aminomethyl, N-(4-chlorophenyl)-aminomethyl,N-(3-methylcarbonylamino-phenyl)-aminomethyl,N-(4-methylcarbonylamino-phenyl)-aminomethyl,N-(2-aminophenyl)-aminomethyl, N-(3-aminophenyl)-aminomethyl,N-(4-aminophenyl)-aminomethyl,N-(2-methylsulfonylaminophenyl)-aminomethyl,N-(3-methylsulfonylaminophenyl)-aminomethyl,N-(4-methylsulfonylaminophenyl)-aminomethyl,N-(2-fluoro-4-hydroxy-phenyl)-aminomethyl,N-(3-fluoro-4-hydroxy-phenyl)-aminomethyl, N-(benzyl)-aminomethyl,N-(2-hydroxyphenylmethyl)-aminomethyl,N-(3-hydroxyphenylmethyl)-aminomethyl,N-(4-hydroxyphenylmethyl)-aminomethyl,N-(2-(N-methylpiperazin-1-yl)-phenylmethyl)-aminomethyl,NV-(4-methyl-phenethyl)-aminomethyl,N-(1-hydroxy-3-phenyl-prop-2-yl)-aminomethyl,N-(pyrrolidin-2-ylmethyl)-aminomethyl,N-(N-ethyl-pyrrolidinylmethyl)-aminomethyl,N-(N-methyl-pyrrolidin-2-ylethyl)-aminomethyl,N-(pyrrolidinylpropyl)-aminomethyl,N-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-aminomethyl,N-(tetrahydrofuranylmethyl)-aminomethyl,N-(tetrahydro-2H-pyran-4-ylmethyl)-aminomethyl,N-(tetrahydro-2H-pyranylethyl)-aminomethyl,N-(piperidin-4-ylmethyl)-aminomethyl,N-(N-methylpiperidin-4-ylmethyl)-aminomethyl,N-(N-tert-butoxycarbonylpiperidin-4-ylmethyl)-aminomethyl,N-(N-methylimidazol-5-ylmethyl)-aminomethyl,N-(N-methylimidazol-4-ylmethyl)-aminomethyl,N-[2-(imidazol-4-yl)-ethyl]-aminomethyl,N-[3-(imidazolyl)-propyl]-aminomethyl,N-(pyridin-3-ylethyl)-aminomethyl, N-(pyridin-4-ylethyl)-aminomethyl,N-(thien-2-ylethyl)-aminomethyl, N-(furan-2-ylethyl)-aminomethyl,N-(5-methyl-1,3,4-oxadiazol-2-ylmethyl)-aminomethyl,N-(2-indolin-3-ylethyl)-aminomethyl,2-(N,N-dimethylamino)-ethylaminomethyl,2-(N,N-dimethylamino)-1-methyl-ethylaminomethyl,3-aminopropylaminomethyl, 3-(N,N-dimethylamino)-propylaminomethyl,3-(N,N-diethylamino)-propylaminomethyl, N-(N,Ndiisopropylaminoethyl)-aminomethyl,N-(N-dimethylaminobutyl)-aminomethyl, 3-hydroxypropylaminomethyl,N-(1,2-dihydroxypropyl)-aminomethyl,N-(1-amino-2-hydroxy-prop-3-yl)-aminomethyl,N-(N-ethoxycarbonyl-piperidin-4-yl)-aminomethyl,N-(N-benzylpiperidin-4-yl)-aminomethyl,N-(homopiperidin-3-yl)-aminomethyl,N-(N-benzylpyrrolidin-3-yl)-aminomethyl,N(N-ethylpiperidin-3-yl)aminomethyl, 2,2,2-trifluoroethylaminomethyl,3,3,3-trifluoropropylaminomethyl,2,2,3,3,3-pentafluoropropylaminomethyl, —CH₂N(CH₂CH₂OH)₂,—CH₂N(CH₃)(CH_(Z)CH_(Z)OH), —CH₂NH(CH₂CH₂OH), —CH₂NH(CH₂CH₂CH₂CH₂OH),—CH₂NH(C(CH₃)₂CH₂OH), —CH₂N(CH₃)(N-methyl-pyrrolidin-3-yl), —C(O)NH₂,—C(O)NHCH₂CH═CH₂, —C(O)NHCH₂CH(OH)CH₂OH, N-(phenyloxyethyl)-aminomethyl,—CH₂NHC(O)CH₃, —CH(CH₃)NHC(O)CH₃, —CH(CH₃)NHC(O)C(OCH₃)(CF₃)phenyl,cyclopentyl, 1-amino-cyclopentyl, (cis,trans)-2-amino-cyclopentyl,(cis,trans)-2-amino-cyclopentyl, cis-2-amino-cyclopentyl,trans-2-amino-cyclopentyl, (cis,trans)-2-hydroxy-cyclohexyl,cis-2-hydroxy-cyclohexyl, trans-2-hydroxy-cyclohexyl,(cis,trans)-2-amino-cyclohexyl, cis-2-amino-cyclohexyl,trans-2-amino-cyclohexyl, azetidin-3-yl, pyrrolidinyl,N-methyl-pyrrolidin-2-yl, N-ethyl-pyrrolidin-2-yl,3-(dimethylamino)-pyrrolidinyl, piperidinyl, 2-methyl-piperidin-6-yl,N-methylpiperidin-2-yl, N-tert-butoxycarbonylpiperidin-2-yl,piperazin-2-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, imidazol-1-yl,imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, N-methyl-imidazol-2-yl,5-methyl-imidazol-2-yl, 1,2,4-triazol-3-yl, thiazol-2-yl,2-aminopyrimidin-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,benzimidazolyl, imidazol-1-ylmethyl, imidazol-2-ylmethyl,triazol-1-ylmethyl, (5-amino-3-methyl-pyrazol-3-yl)-methyl,phenoxymethyl, 2-hydroxyethyloxymethyl, methylsulfonylaminomethyl,1-(methoxycarbonylamino)-ethyl, 1-amino-1-phenyl-methyl, or1-amino-3-hydroxy-propyl.

Another specific embodiment of the Invention (A11) is that where thecompound of Formula I is selected from Group A where R³ and R⁴ togetherwith the carbon to which they are attached form C(O) or C(═NOH). Morespecifically, X and R⁷ are halo; A is phenylene optionally substitutedwith R¹‘ and R’² where R¹⁰ and R¹² are independently hydrogen or halo;R¹, R², R⁵ and R⁶ are hydrogen; and R³ and R⁴ together with the carbonto which they are attached form C(O) or C(═NOH).

Another specific embodiment of the Invention (A12) is that where thecompound of Formula I is selected from Group A where X and R⁷ are halo;A is phenylene optionally substituted with R¹⁰ and R¹² where R¹⁰ and R¹²are independently hydrogen or halo; and R¹, R², R⁴, R⁵ and R⁶ arehydrogen.

Another specific embodiment of the Invention (A13) is that where thecompound of Formula I is selected from Group A where A is phenylene.

Another specific embodiment of the Invention (A14) is that where thecompound of Formula I is selected from Group A where R′ is hydrogen andR² is alkyl substituted with —NR⁸R^(8′) where R⁸ and R^(8′) and allother groups are as defined in the Summary of the Invention for acompound of Group A.

Another specific embodiment of the Invention (A15) is that where thecompound of Formula I is selected from Group A where A is phenylene; R⁷is iodo or bromo; X is fluoro or chloro; and R¹, R², R⁵, and R⁶ arehydrogen; and R¹⁰, R¹², R¹⁴, and R¹⁶ are independently hydrogen orfluoro. More specifically, R¹⁰ is 3-fluoro and R¹², R¹⁴, and R¹⁶ arehydrogen or halo; R¹⁰ is 3-fluoro, R¹² is 4-fluoro, and R¹⁴ and R¹⁶ arehydrogen; R¹⁰ is 4-fluoro, R¹² is 5-fluoro, and R¹⁴ and R¹⁶ arehydrogen; R¹⁰ is 4-fluoro, R¹² is 6-fluoro, and R¹⁴ and R¹⁶ arehydrogen; or R¹² is 4-fluoro and R¹⁰, R¹⁴, and R¹⁶ are hydrogen.

In another embodiment of the invention is a compound of Formula selectedform Group A where R³ is hydroxy and R⁴ is heterocycloalkyl, alkyl, orheteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′)(where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, orcycloalkyl where the cycloalkyl is optionally substituted with groupsindependently selected from hydroxy and alkyl) and the heteroaryl isoptionally substituted with alkyl. Specifically, R³ is hydroxy and R⁴ isheterocycloalkyl or alkyl, where the alkyl is optionally substitutedwith —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen,alkyl, or cycloalkyl where the cycloalkyl is optionally substituted withgroups independently selected from hydroxy and alkyl).

In another embodiment of the Invention (B1) the compound of Formula I isselected from Group B where all groups are as defined in the Summary ofthe Invention.

In another embodiment of the invention (B2), X and R⁷ are halo; and allother groups are as defined in the Summary of the Invention for acompound of Group B. Specifically, X is fluoro or chloro and R⁷ is iodoor bromo.

In another embodiment of the invention (B33), the compound is selectedfrom Group B where R³ is halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN,—S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),—NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),—CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN)),—CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl,alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl areindependently optionally substituted with one, two, three, four, five,six or seven groups independently selected from halo, alkyl, haloalkyl,nitro, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″),—NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′) and R⁴ is as defined in the Summaryof the Invention; or R³ and R⁴ together with the carbon to which theyare attached form C(O) or C(═NOH); and all other groups are as definedin the Summary of the Invention for a compound of Group B. Morespecifically, R¹, R², R⁵ and R⁶ are hydrogen; and X and R⁷ are halo.

In another embodiment of the invention (14), the compound is selectedfrom Group B where R³ and R⁴ are independently halo, nitro, —NR⁸R^(8′),—OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸,—S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′),—NR⁸C(O)R^(8′), —CH₂N(R²⁵)(NR^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)),—CH₂NR²⁵C(═NH)(N(R^(25a))(CN)), —CH₂NR²⁵C(═NH)(R²⁵),—CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl, cycloalkyl,heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl,cycloalkyl, heteroaryl, and heterocycloalkyl are independentlyoptionally substituted with one, two, three, four, five, six or sevengroups independently selected from halo, alkyl, haloalkyl, nitro,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NRS(O)₂R⁹, —CN, —S(O)_(m)R⁹,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″),—NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or R³ and R⁴ together with thecarbon to which they are attached form C(O) or C(═NOH); and all othergroups are as defined in the Summary of the Invention for a compound ofGroup B. More specifically, R¹, R², R⁵ and R⁶ are hydrogen; and X and R⁷are halo.

In another embodiment of the invention (B5), A is heteroarylene selectedfrom thien-diyl, benzo[d]isoxazol-diyl, benzo[d]isothiazol-diyl,1H-indazol-diyl (optionally substituted at the N1 position with R¹⁹where R¹⁹ is as defined in the Summary of the Invention for a compoundof Group B), benzo[d]oxazol-diyl, benzo[d]thiazol-diyl,1H-benzo[d]imidazol-diyl (optionally substituted at the N1 position withR¹⁹ where R¹⁹ is as defined in the Summary of the Invention for acompound of Group B), 1H-benzo[d][1,2,3]triazol-diyl (optionallysubstituted at the N1 position with R¹⁹ where R¹⁹ is as defined in theSummary of the Invention for a compound of Group B),imidazo[1,2-a]pyridin-diyl, cinnolin-diyl, quinolin-diyl, pyridin-diyl,1-oxido-pyridin-diyl, [1,2,4]triazolo[4,3-a]pyridin-diyl, and2,3-dihydroimidazo[1,2-a]pyridin-diyl; and A is further optionallysubstituted with one, two, three, or four groups selected from R¹⁰, R¹²,R¹⁴, and R¹⁶ where R¹⁰, R¹², R¹⁴, and R¹⁶ and all other groups are asdefined in the Summary of the Invention for a compound of Group B. Morespecifically A is selected from thien-3,4-diyl,benzo[d]isoxazol-5,6-diyl, benzo[d]isothiazol-5,6-diyl,1H-indazol-5,6-diyl (optionally substituted at the N1 position with R¹⁹where R¹⁹ is alkyl or alkenyl), benzo[d]oxazol-5,6-diyl,benzo[d]thiazol-5,6-diyl, 1H-benzo[d]imidazol-5,6-diyl (optionallysubstituted at the N1 position with R¹⁹ where R¹⁹ is alkyl or alkenyl),1H-benzo[d][1,2,3]triazol-5,6-diyl (optionally substituted at the N1position with R¹⁹ where R¹⁹ is alkyl or alkenyl),imidazo[1,2-a]pyridin-5,6-diyl, cinnolin-6,7-diyl, quinolin-6,7-diyl,pyridin-3,4-diyl, 1-oxido-pyridin-3,4-diyl,[1,2,4]triazolo[4,3-a]pyridin-6,7-diyl, and2,3-dihydroimidazo[1,2-a]pyridin-6,7-diyl.

In another embodiment of the Invention (86), the compound of Formula Iis selected from Group B where A is thien-diyl and X, R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R¹⁰, and R¹² are as defined in the Summary of the Inventionfor a compound of Group B. More specifically A is thien-3,4-diyl; R¹⁰and R¹² are hydrogen; X and R⁷ are halo; and R¹, R², R⁵, and R arehydrogen. Even more specifically, X is fluoro or chloro; R⁷ is iodo orbromo; R³ is hydrogen or hydroxy; and R⁴ is —NR⁸R^(8′) (where R⁸ andR^(8′) are independently hydrogen or alkyl), heterocycloalkyl,heteroaryl (optionally substituted with alkyl), or alkyl where the alkylis optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyland R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl isoptionally substituted with one or two groups independently selectedfrom hydroxy and alkyl).

In another embodiment (B7), the compound is of Formula I(c) or I(d)

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹² and R¹⁴ are as defined inthe Summary of the Invention for a compound of Group B. Morespecifically, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ andR⁴ are as defined in the Summary of the Invention for Group B; and R¹⁰,R¹², and R¹⁴ are independently hydrogen, halo, or alkyl. Even morespecifically, X is fluoro or chloro and R⁷ is iodo or bromo; R¹⁰ ishydrogen or halo, more specifically hydrogen or fluoro; R¹² is hydrogen;R¹⁴ is hydrogen or alkyl; and R³ is hydroxy. Yet even more specifically,R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl isoptionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyland R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl isoptionally substituted with groups independently selected from hydroxyand alkyl) and the heteroaryl is optionally substituted with alkyl. Yeteven more specifically, R⁴ is piperidinyl, pyrrolidinyl,1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl,1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl,1(S)-(methylamino)-ethyl, 1(R,S)-(dimethylamino)-ethyl,1(R)-(dimethylamino)-ethyl, 1(S)-(dimethylamino)-ethyl,1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl,1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In another embodiment of the Invention (138), the compound is of FormulaI(e) or I(f):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹² and R¹⁴ are as defined inthe Summary of the Invention for a compound of Group B. Morespecifically, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ andR⁴ are as defined in the Summary of the Invention for Group B; and

-   R¹⁰, R¹², and R¹⁴ are independently hydrogen, halo, or alkyl. Even    more specifically, X is fluoro or chloro and R⁷ is iodo or bromo;    R¹⁰ is hydrogen or halo, more specifically hydrogen or fluoro; R¹²    and R¹⁴ are hydrogen; R³ is hydroxy; and R⁴ is heterocycloalkyl,    alkyl, or heteroaryl, where the alkyl is optionally substituted with    —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen,    alkyl, or cycloalkyl where the cycloalkyl is optionally substituted    with one or two groups independently selected from hydroxy and    alkyl) and the heteroaryl is optionally substituted with alkyl.

In another embodiment of the Invention (B9), the compound is of FormulaI(g) or I(h):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹², R¹⁴, and R¹⁹ are asdefined in the Summary of the Invention for a compound of Group B.

In a more specific embodiment of embodiment B9, the compound is offormula I(g) or I(h) where

-   R³ is halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸,    —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),    —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),    —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵SC(═NH)(N(R^(25a))(CN)),    —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), cycloalkyl,    heteroaryl, or heterocycloalkyl; where the cycloalkyl, heteroaryl,    and heterocycloalkyl are optionally substituted with one, two,    three, four, five, six or seven groups independently selected from    halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl,    optionally substituted heterocycloalkyl, optionally substituted    aryl, optionally substituted arylalkyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, heteroarylalkyl,    —OR⁸, —NR⁸R^(8′), —NRS(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸,    —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and    —NR⁸C(O)R^(8′); and R⁴ is as defined in the Summary of the    Invention; or R³ and R⁴ together with the carbon to which they are    attached form C(O) or C(NOH); and    all other groups are as defined in the Summary of the Invention for    a compound of Group B.

In a more specific embodiment of embodiment B9, the compound is offormula I(g) or I(h) where R³ is hydroxy and all other groups are asdefined in the Summary of the Invention for a compound of Group B.

In a more specific embodiment of embodiment B9, the compound is offormula I(g) or I(h) where R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ arehalo; R³ and R⁴ are as defined in the Summary of the Invention for GroupB; R¹⁰, R¹², and R¹⁴ are independently hydrogen, halo, or alkyl; and R¹⁹is hydrogen or methyl. Even more specifically, X is fluoro or chloro andR⁷ is iodo or bromo; R¹⁰ is hydrogen or halo, more specifically hydrogenor fluoro; R¹² and R¹⁴ are hydrogen; R³ is hydroxy; and R⁴ isheterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionallysubstituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) ishydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionallysubstituted with one or two groups independently selected from hydroxyand alkyl) and the heteroaryl is optionally substituted with alkyl.

In another embodiment of the Invention (B10), the compound is of FormulaI(i) or I(j):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹² and R¹⁴ are as defined inthe Summary of the Invention for a compound of Group B. Morespecifically, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ andR⁴ are as defined in the Summary of the Invention for Group B; and R¹⁰,R¹², and R¹⁴ are independently hydrogen, halo, or alkyl. Even morespecifically, X is fluoro or chloro and R⁷ is iodo or bromo; R¹⁰ ishydrogen or halo, more specifically hydrogen or fluoro; R¹² and R¹⁴ arehydrogen; R³ is hydroxy; and R⁴ is heterocycloalkyl, alkyl, orheteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′)(where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, orcycloalkyl where the cycloalkyl is optionally substituted with one ortwo groups independently selected from hydroxy and alkyl) and theheteroaryl is optionally substituted with alkyl.

In another embodiment of the Invention (B11), the compound is of FormulaI(k) or I(m):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹² and R¹⁴ are as defined inthe Summary of the Invention for a compound of Group B. Morespecifically, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ andR⁴ are as defined in the Summary of the Invention for Group B; and R¹⁰,R¹², and R¹⁴ are independently hydrogen, halo, or alkyl. Even morespecifically, X is fluoro or chloro and R⁷ is iodo or bromo; R¹⁰ ishydrogen or halo, more specifically hydrogen or fluoro; R¹² and R¹⁴ arehydrogen; R³ is hydroxy; and R⁴ is heterocycloalkyl, alkyl, orheteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′)(where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, orcycloalkyl where the cycloalkyl is optionally substituted with one ortwo groups independently selected from hydroxy and alkyl) and theheteroaryl is optionally substituted with alkyl.

In another embodiment of the Invention (B12), the compound is of FormulaI(n) or I(o):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹², R¹⁴, and R¹⁹ are asdefined in the Summary of the Invention for a compound of Group B.

In a more specific embodiment of embodiment B12, the compound is offormula I(n) or I(o) where R⁷ is halo or alkyl; and all other groups areas defined in the Summary of the Invention for a compound of Group B.More specifically, R⁷ is iodo or bromo.

In a more specific embodiment of embodiment B12, the compound is offormula I(n) or I(o) where X is halo, haloalkyl, or haloalkoxy; and allother groups are as defined in the Summary of the Invention for acompound of Group B. More specifically, X is halo. Even morespecifically X is fluoro or chloro.

In a more specific embodiment of embodiment B12, the compound is offormula I(n) or I(o) where

-   R³ is halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸,    —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),    —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),    —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵SC(═NH)(N(R^(25a))(CN)),    —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl,    alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where    the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and    heterocycloalkyl are independently optionally substituted with one,    two, three, four, five, six or seven groups independently selected    from halo, alkyl, haloalkyl, nitro, optionally substituted    cycloalkyl, optionally substituted heterocycloalkyl, optionally    substituted aryl, optionally substituted arylalkyl, optionally    substituted heteroaryl, optionally substituted heteroarylalkyl,    —OR⁸, —NR⁸R^(8′), —NRS(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸,    —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and    —NR⁸C(O)R^(8′); and R⁴ is as defined in the Summary of the    Invention; or    R³ and R⁴ together with the carbon to which they are attached form    C(O) or C(═NOH); and unless otherwise indicated, R⁸ and R^(8′) are    as defined in the Summary of the Invention; and all other groups are    as defined in the Summary of the Invention for a compound of Group    B.

In a more specific embodiment of embodiment B12, the compound is offormula I(n) or I(o) where R¹⁹ is alkyl; R¹, R², R⁵, and R⁶ arehydrogen; X and R⁷ are halo; R³ and R⁴ arc as defined in the Summary ofthe Invention for Group H; and R¹⁰, R¹², and R¹⁴ are independentlyhydrogen or halo. Even more specifically, R¹⁹ is methyl; X is fluoro orchloro and R⁷ is iodo or bromo; R¹⁰ is hydrogen or fluoro; R¹² and R¹⁴are hydrogen; and R³ is hydroxy. Yet even more specifically, R⁴ isheterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionallysubstituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) ishydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionallysubstituted with one or two groups independently selected from hydroxyand alkyl) and the heteroaryl is optionally substituted with alkyl. Yeteven more specifically, R⁴ is piperidinyl, pyrrolidinyl,I(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl,1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl,1(S)-(methylamino)-ethyl, 1(R,S)-(dimethylamino)-ethyl,1(R)-(dimethylamino)-ethyl, 1(S)-(dimethylamino)-ethyl,1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl,1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In another embodiment of the Invention (B13), the compound is of FormulaI(p):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹², and R¹⁹ are as defined inthe Summary of the Invention for a compound of Group B. Morespecifically, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ andR⁴ are as defined in the Summary of the Invention for Group B; and R¹⁰and R¹² are independently hydrogen, halo, or alkyl. Even morespecifically, X is fluoro or chloro; R⁷ is iodo or bromo; R¹⁰ ishydrogen or halo, more specifically hydrogen or fluoro; R¹² is hydrogen;R¹⁹ is hydrogen or alkyl, more specifically hydrogen or methyl; R³ ishydroxy. Even more specifically, R⁴ is heterocycloalkyl, alkyl, orheteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′)(where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl, orcycloalkyl where the cycloalkyl is optionally substituted with one ortwo groups independently selected from hydroxy and alkyl) and theheteroaryl is optionally substituted with alkyl. Yet even morespecifically, R⁴ is piperidinyl, pyrrolidinyl, 1(R,S)-amino-ethyl,1(R)-amino-ethyl, 1(S)-amino-ethyl, 1(R,S)-(methylamino)-ethyl,1(R)-(methylamino)-ethyl, 1(S)-(methylamino)-ethyl,1(R,S)-(dimethylamino)-ethyl, 1(R)-(dimethylamino)-ethyl,1(S)-(dimethylamino)-ethyl,1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl,1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In another embodiment of the Invention (B14), the compound is of FormulaI(q):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹² R¹⁴, and R¹⁶ are asdefined in the Summary of the Invention for a compound of Group B.

In a more specific embodiment of embodiment B14, the compound is offormula I(q) where

-   R³ is halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸,    —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),    —CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),    —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵SC(═NH)(N(R^(25a))(CN)),    —CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl,    alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where    the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and    heterocycloalkyl are independently optionally substituted with one,    two, three, four, five, six or seven groups independently selected    from halo, alkyl, haloalkyl, nitro, optionally substituted    cycloalkyl, optionally substituted heterocycloalkyl, optionally    substituted aryl, optionally substituted arylalkyl, optionally    substituted heteroaryl, optionally substituted heteroarylalkyl,    —OR⁸, —NR⁸R^(8′), —NRS(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸,    —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and    —NR⁸C(O)R^(8′); and R⁴ is as defined in the Summary of the    Invention; or    R³ and R⁴ together with the carbon to which they are attached form    C(O) or C(═NOH); and all other groups are as defined in the Summary    of the Invention for a compound of Group B.

in a more specific embodiment of embodiment B14, the compound is offormula I(q) where R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo;R³ and R⁴ are as defined in the Summary of the Invention for Group B;and R¹⁰, R¹², R¹⁴, and R¹⁶ are independently hydrogen or halo. Even morespecifically, R¹⁰ is halo and R¹², R¹⁴, and R¹⁶ are hydrogen. Even morespecifically, X is fluoro or chloro; R⁷ is iodo or bromo; R¹⁰ is chloro;and R³ is hydroxy. Even more specifically, R⁴ is heterocycloalkyl,alkyl, or heteroaryl, where the alkyl is optionally substituted with—NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl,or cycloalkyl where the cycloalkyl is optionally substituted with one ortwo groups independently selected from hydroxy and alkyl) and theheteroaryl is optionally substituted with alkyl. Yet even morespecifically, R⁴ is piperidinyl, pyrrolidinyl, benzimidazolyl,1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl,1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl,1(S)-(methylamino)-ethyl,1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl,1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In another embodiment of the Invention (B15), the compound is of FormulaI(r):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹² and R¹⁴ are as defined inthe Summary of the Invention for a compound of Group B. Morespecifically, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ andR⁴ are as defined in the Summary of the Invention for Group B; R¹⁰ andR¹² are independently hydrogen, halo, or alkyl; and R¹⁴ is hydrogen,halo, alkyl, or amino. Even more specifically, X is fluoro or chloro; R⁷is iodo or bromo; R¹⁰ is hydrogen or halo, more specifically hydrogen orfluoro; R¹² is hydrogen; R¹⁴ is hydrogen, alkyl, or amino, morespecifically hydrogen, methyl, or amino; R³ is hydroxy. Even morespecifically, R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where thealkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen oralkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkylis optionally substituted with one or two groups independently selectedfrom hydroxy and alkyl) and the heteroaryl is optionally substitutedwith alkyl. Yet even more specifically, R⁴ is piperidinyl, pyrrolidinyl,1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl,1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl,1(S)-(methylamino)-ethyl,1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl,1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In another embodiment of the Invention (B16), the compound is of FormulaI(s):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹² and R¹⁴ are as defined inthe Summary of the Invention for a compound of Group B. Morespecifically, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ andR⁴ are as defined in the Summary of the Invention for Group B; and R¹⁰and R¹² are independently hydrogen, halo, or alkyl; and R¹⁴ is hydrogen,halo, alkyl, or amino. Even more specifically, X is fluoro or chloro andR⁷ is iodo or bromo; R¹⁰ is hydrogen or halo, more specifically hydrogenor fluoro; R¹² is hydrogen; R¹⁴ is hydrogen, methyl, or amino; R³ ishydroxy; and R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where thealkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen oralkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkylis optionally substituted with one or two groups independently selectedfrom hydroxy and alkyl) and the heteroaryl is optionally substitutedwith alkyl.

In another embodiment of the Invention (B18), the compound is of FormulaI(u), I(v), I(w), or I(x):

where X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹² and R¹⁴ are as defined inthe Summary of the Invention for a compound of Group B.

In a more specific embodiment of embodiment B18, the compound is offormula I(u), I(v), I(w), or I(x) where R³ is halo, nitro, —NR⁸R^(8′),—OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR⁸R^(8″), —NR⁸C(O)OR^(8′),—NR⁸C(O)R^(8′), —CH₂N(R²⁵)(R^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)),—CH₂NR²⁵C(═NH)(N(R^(25a))(CN)), —CH₂NR²⁵C(═NH)(R²⁵),—CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl, cycloalkyl,heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl,cycloalkyl, heteroaryl, and heterocycloalkyl are independentlyoptionally substituted with one, two, three, four, five, six or sevengroups independently selected from halo, alkyl, haloalkyl, nitro,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)R⁹, —C(O)R⁸,—C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and—NR⁸C(O)R^(8′); and R⁴ is as defined in the Summary of the Invention fora compound of Group B; or R³ and R⁴ together with the carbon to whichthey are attached form C(O) or C(═NOH); and all other groups are asdefined in the Summary of the Invention for a compound of Group B.

In a more specific embodiment of embodiment B18, the compound is offormula I(t), I(u), I(v), or I(w) where R³ and R⁴ are independentlyhalo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸,—S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),—NR⁸C(O)NR⁸R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),—CH₂N(R²⁵)(R^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN)),—CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl,alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl areindependently optionally substituted with one, two, three, four, five,six or seven groups independently selected from halo, alkyl, haloalkyl,nitro, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″),—NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or R³ and R⁴ together with thecarbon to which they are attached form C(O) or C(═NOH); and all othergroups are as defined in the Summary of the Invention for a compound ofGroup B.

In a more specific embodiment of embodiment B18, the compound is offormula I(u), I(v), I(w), or I(x) where R⁴ is heterocycloalkyl,heteroaryl (optionally substituted with alkyl), or alkyl where the alkylis optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyland R⁴ is hydrogen, alkyl, or cycloalkyl where the cycloalkyl isoptionally substituted with one or two groups independently selectedfrom hydroxy and alkyl). More specifically, R⁴ is piperidinyl,pyrrolidinyl, 1(R,S)-amino-propyl, 1(R)-amino-propyl, 1(S)-amino-propyl,1(R,S)-(methylamino)-propyl, 1(R)-(methylamino)-propyl,1(S)-(methylamino)-propyl,1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-propyl,1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-propyl, or1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-propyl.

In a more specific embodiment of embodiment B18, the compound is offormula I(u), I(v), I(w), or I(x) where R¹, R², R⁵, and R⁶ are hydrogen;X and R⁷ are halo; R³ and R⁴ arc as defined in the Summary of theInvention for Group B; and R¹⁰, R¹², and R¹⁴ are independently hydrogen,halo, or alkyl. Even more specifically, X is fluoro or chloro; R⁷ isiodo or bromo; R¹⁰ is hydrogen or halo, more specifically hydrogen orfluoro; R¹² and R¹⁴ are hydrogen; and R³ is hydroxy. Even morespecifically R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where thealkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen oralkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkylis optionally substituted with one or two groups independently selectedfrom hydroxy and alkyl) and the heteroaryl is optionally substitutedwith alkyl.

In another embodiment of the Invention (B19), the compound is of FormulaI(cc)

where X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined in the Summary ofthe Invention for a compound of Group B. Specifically, R¹, R², R⁵, andR⁶ are hydrogen; and X and R⁷ are halo. More specifically, X is fluoroor chloro; and R³ is hydrogen or hydroxy; R⁷ is iodo or bromo. Even morespecifically, R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where thealkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen oralkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkylis optionally substituted with one or two groups independently selectedfrom hydroxy and alkyl) and the heteroaryl is optionally substitutedwith alkyl. Yet even more specifically, R⁴ is piperidinyl, pyrrolidinyl,benzimidazolyl, N-methyl-benzimidazolyl, methylaminomethyl,1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl,1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl,1(S)-(methylamino)-ethyl, 1(R,S)-(dimethylamino)-ethyl,1(R)-(dimethylamino)-ethyl, 1(S)-(dimethylamino)-ethyl,1(R,S)-amino-propyl, 1(R)-amino-propyl, 1(S)-amino-propyl,1(R,S)-(methylamino)-propyl, 1(R)-(methylamino)-propyl,1(S)-(methylamino)-propyl, 1(R,S)-(dimethylamino)-propyl,1(R)-(dimethylamino)-propyl, 1(S)-(dimethylamino)-propyl,1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl,1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In a specific embodiment (B19a) of embodiment B19 is that where R⁴ isheterocycloalkyl or alkyl where the alkyl is optionally substituted with—NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl,or cycloalkyl where the cycloalkyl is optionally substituted with one ortwo groups independently selected from hydroxy and alkyl). Specifically,R⁴ is piperidinyl, pyrrolidinyl, methylaminomethyl, 1(R,S)-amino-ethyl,1(R)-amino-ethyl, 1(S)-amino-ethyl, 1(R,S)-(methylamino)-ethyl,1(R)-(methylamino)-ethyl, 1(S)-(methylamino)-ethyl,1(R,S)-(dimethylamino)-ethyl, 1(R)-(dimethylamino)-ethyl,1(S)-(dimethylamino)-ethyl, 1(R,S)-amino-propyl, 1(R)-amino-propyl,1(S)-amino-propyl, 1(R,S)-(methylamino)-propyl,1(R)-(methylamino)-propyl, 1(S)-(methylamino)-propyl,1(R,S)-(dimethylamino)-propyl, 1(R)-(dimethylamino)-propyl,1(S)-(dimethylamino)-propyl,1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl,1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In another embodiment of the Invention (B20), the compound is of FormulaI(dd)

where X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined in the Summary ofthe Invention for a compound of Group B. Specifically, R¹, R², R⁵, andR⁶ are hydrogen; and X and R⁷ are halo. More specifically, X is fluoroor chloro; and R³ is hydrogen or hydroxy; R⁷ is iodo or bromo. Even morespecifically, R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where thealkyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen oralkyl and R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkylis optionally substituted with one or two groups independently selectedfrom hydroxy and alkyl) and the heteroaryl is optionally substitutedwith alkyl. Yet even more specifically, R⁴ is piperidinyl, pyrrolidinyl,benzimidazolyl, N-methyl-benzimidazolyl, methylaminomethyl,1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl,1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl,1(S)-(methylamino)-amino)-ethyl, 1(R,S)-(dimethylamino)-ethyl,1(R)-(dimethylamino)-ethyl, 1(S)-(dimethylamino)-ethyl,1(R,S)-amino-propyl, 1(R)-amino-propyl, 1(S)-amino-propyl,1(R,S)-(methylamino)-propyl, 1(R)-(methylamino)-propyl,1(S)-(methylamino)-propyl, 1(R,S)-(dimethylamino)-propyl,1(R)-(dimethylamino)-propyl, 1(S)-(dimethylamino)-propyl,1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl,1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In a specific embodiment (B20a) of embodiment B20 is that where R⁴ isheterocycloalkyl or alkyl where the alkyl is optionally substituted with—NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen, alkyl,or cycloalkyl where the cycloalkyl is optionally substituted with one ortwo groups independently selected from hydroxy and alkyl). Specifically,R⁴ is piperidinyl, pyrrolidinyl, methylaminomethyl, 1(R,S)-amino-ethyl,1(R)-amino-ethyl, 1(S)-amino-ethyl, 1(R,S)-(methylamino)-ethyl,1(R)-(methylamino)-ethyl, 1(S)-(methylamino)-ethyl,1(R,S)-(dimethylamino)-ethyl, 1(R)-(dimethylamino)-ethyl,1(S)-(dimethylamino)-ethyl, 1(R,S)-amino-propyl, 1(R)-amino-propyl,1(S)-amino-propyl, 1(R,S)-(methylamino)-propyl,1(R)-(methylamino)-propyl, 1(S)-(methylamino)-propyl,1(R,S)-(dimethylamino)-propyl, 1(R)-(dimethylamino)-propyl,1(S)-(dimethylamino)-propyl,I(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl,1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In one embodiment of the Invention (C1), the compound of Formula I isselected from Group C where all groups are as defined in the Summary ofthe Invention.

In another embodiment of the invention (C2), X and R⁷ are halo; and allother groups are as defined for a compound selected from Group C.

In another embodiment of the invention (C3), the compound is selectedfrom Group C where R³ is halo, nitro, halo, nitro, —NR⁸R^(8′), —OR⁸,—NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR⁸R^(8″), —NR⁸C(O)OR^(8′),—NR⁸C(O)R^(8′), —CH₂N(R²⁵)(R^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)),—CH₂NR²⁵C(═NH)(N(R^(25a))(CN)), —CH₂NR²⁵C(═NH)(R²⁵),—CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl, cycloalkyl,heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl,cycloalkyl, heteroaryl, and heterocycloalkyl are independentlyoptionally substituted with one, two, three, four, five, six or sevengroups independently selected from halo, alkyl, haloalkyl, nitro,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″),—NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); and R⁴ is as defined in the Summaryof the Invention; or R³ and R⁴ together with the carbon to which theyare attached form C(O) or C(═NOH); and all other groups are as definedin the Summary of the Invention for a compound of Group C. Morespecifically, R¹, R², R⁵ and R⁶ are hydrogen; and X and R⁷ are halo.

In another embodiment of the invention (C4), the compound is selectedfrom Group C where R³ and R⁴ are independently halo, nitro, —NR⁸R^(8′),—OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR⁸R^(8″), —NR⁸C(O)OR^(8′),—NR⁸C(O)R^(8′), —CH₂N(R²⁵)(R^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)),—CH₂NR²⁵C(═NH)(N(R^(25a))(CN)), —CH₂NR²⁵C(═NH)(R²⁵),—CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl, cycloalkyl,heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl,cycloalkyl, heteroaryl, and heterocycloalkyl are independentlyoptionally substituted with one, two, three, four, five, six or sevengroups independently selected from halo, alkyl, haloalkyl, nitro,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁸,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″),—NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or R³ and R⁴ together with thecarbon to which they are attached form C(O) or C(═NOH); and all othergroups are as defined in the Summary of the Invention for a compound ofGroup C. More specifically, R¹, R², R⁵ and R⁶ are hydrogen; and X and R⁷are halo.

In another embodiment of the invention (C5), A is

and X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, and R^(10a) are as defined inthe Summary of the invention for a compound of Group C. Morespecifically, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R¹⁰ ishydrogen or halo; and R^(10a) is alkyl. Even more specifically, X isfluoro or chloro; R³ is hydroxy; R⁷ is iodo or bromo; R¹⁰ is hydrogen orfluoro; and R^(10a) is methyl. Even more specifically, R⁴ isheterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionallysubstituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) ishydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionallysubstituted with one or two groups independently selected from hydroxyand alkyl) and the heteroaryl is optionally substituted with alkyl. Yeteven more specifically, R⁴ is piperidinyl, pyrrolidinyl, benzimidazolyl,N-methyl-benzimidazolyl, methylaminomethyl, 1(R,S)-amino-ethyl,1(R)-amino-ethyl, 1(S)-amino-ethyl, 1(R,S)-(methylamino)-ethyl,1(R)-(methylamino)-ethyl, 1(S)-(methylamino)-ethyl,1(R,S)-(dimethylamino)-ethyl, 1(R)-(dimethylamino)-ethyl,1(S)-(dimethylamino)-ethyl, 1(R,S)-amino-propyl, 1(R)-amino-propyl,1(S)-amino-propyl, 1(R,S)-(methylamino)-propyl,1(R)-(methylamino)-propyl, 1(S)-(methylamino)-propyl,1(R,S)-(dimethylamino)-propyl, 1(R)-(dimethylamino)-propyl,1(S)-(dimethylamino)-propyl,1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl,1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In another embodiment of the invention (C6), A is

and X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, and R^(10a) are as defined inthe Summary of the invention for a compound of Group C. Morespecifically, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R¹⁰ ishydrogen or halo; and R^(10a) is alkyl. Even more specifically, X isfluoro or chloro; R³ is hydroxy; R⁷ is iodo or bromo; R¹⁰ is hydrogen orfluoro; and R^(10a) is methyl. Even more specifically, R⁴ isheterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionallysubstituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) ishydrogen, alkyl, or cycloalkyl where the cycloalkyl is optionallysubstituted with one or two groups independently selected from hydroxyand alkyl) and the heteroaryl is optionally substituted with alkyl. Yeteven more specifically, R⁴ is piperidinyl, pyrrolidinyl, benzimidazolyl,N-methylbenzimidazolyl, 1(R,S)-amino-ethyl, 1(R)-amino-ethyl,1(S)-amino-ethyl, 1(R,S)-amino-propyl, 1(R)-amino-propyl,1(S)-amino-propyl, 1(R,S)-(methylamino)-propyl,1(R)-(methylamino)-propyl, 1(S)-(methylamino)-propyl,1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-propyl,1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-propyl,1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-propyl,1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl,1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In another embodiment of the Invention (C7), the compound is of FormulaI(y) or I(z):

where R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³, R⁴, R¹⁰,R^(10a), and Y¹ are as defined in the Summary of the Invention for acompound of Group C. In a more specific embodiment, X is fluoro orchloro; R⁷ is iodo or bromo; R¹⁰ is hydrogen, halo, or alkyl, morespecifically hydrogen or halo; and R^(10a) is alkyl, more specificallymethyl Even more specifically R¹⁰ is hydrogen or fluoro; R³ is hydroxy;and R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl isoptionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyland R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl isoptionally substituted with one or two groups independently selectedfrom hydroxy and alkyl) and the heteroaryl is optionally substitutedwith alkyl.

In one embodiment of the Invention (D), the compound of Formula I isselected from Group D where all groups are as defined in the Summary ofthe Invention.

In another embodiment of the invention (D1), X and R⁷ are halo; and allother groups are as defined for a compound selected from Group D.

In another embodiment of the invention (D2), the compound is selectedfrom Group D where R³ is halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN,—S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),—NR⁸C(O)OR^(8′), —NR⁸C(O)NR⁸R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),—CH₂N(R²⁵)(R^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN)),—CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl,alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl areindependently optionally substituted with one, two, three, four, five,six or seven groups independently selected from halo, alkyl, haloalkyl,nitro, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR⁸R^(8″), —NR⁸C(O)OR^(8′)and —NR⁸C(O)R^(8′); and R⁴ is as defined in the Summary of theInvention; or R³ and R⁴ together with the carbon to which they areattached form C(O) or C(═NOH); and all other groups are as defined inthe Summary of the Invention for a compound of Group C. Morespecifically, R¹, R², R⁵ and R⁶ are hydrogen; and X and R⁷ are halo.

In another embodiment of the invention (D3), the compound is selectedfrom Group D where R³ and R⁴ are independently halo, nitro, nitro,—NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′),—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR⁸R^(8″),—NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), —CH₂N(R²⁵)(R^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)),—CH₂NR²⁵C(═NH)(N(R^(25a))(CN)), —CH₂NR²⁵C(═NH)(R²⁵),—CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl, cycloalkyl,heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl,cycloalkyl, heteroaryl, and heterocycloalkyl are independentlyoptionally substituted with one, two, three, four, five, six or sevengroups independently selected from halo, alkyl, haloalkyl, nitro,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′)—NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′)and —NR⁸C(O)R^(8′); or R³ and R⁴ together with the carbon to which theyare attached form C(O) or C(═NOH); and all other groups are as definedin the Summary of the Invention for a compound of Group C. Morespecifically, R¹, R², R⁵ and R⁶ are hydrogen; and X and R′ are halo.

In another embodiment of the invention (D4), A is

where R⁴⁰ is hydrogen or methyl (specifically, R⁴⁰ is hydrogen) and allother groups are as defined in the Summary of the Invention.Specifically, R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; andR⁴⁰ is hydrogen or methyl. More specifically, X is fluoro or chloro; andR³ is hydrogen or hydroxy; R⁷ is iodo or bromo. Even more specifically,R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl isoptionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogen or alkyland R^(8′) is hydrogen, alkyl, or cycloalkyl where the cycloalkyl isoptionally substituted with one or two groups independently selectedfrom hydroxy and alkyl) and the heteroaryl is optionally substitutedwith alkyl. Yet even more specifically, R⁴ is piperidinyl, pyrrolidinyl,benzimidazolyl, N-methyl-benzimidazolyl, methylaminomethyl,1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl,1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl,1(S)-(methylamino)-ethyl, 1(R,S)-(dimethylamino)-ethyl,1(R)-(dimethylamino)-ethyl, l(S)-(dimethylamino)-ethyl,1(R,S)-amino-propyl, 1(R)-amino-propyl, 1(S)-amino-propyl,1(R,S)-(methylamino)-propyl, 1(R)-(methylamino)-propyl,1(S)-(methylamino)-propyl, 1(R,S)-(dimethylamino)-propyl,1(R)-(dimethylamino)-propyl, 1(S)-(dimethylamino)-propyl,1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl,1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

In a specific embodiment (D4a) of the invention of D4 is that where R⁴is heterocycloalkyl or alkyl where the alkyl is optionally substitutedwith —NR⁸R^(8′) (where R⁸ is hydrogen or alkyl and R^(8′) is hydrogen,alkyl, or cycloalkyl where the cycloalkyl is optionally substituted withone or two groups independently selected from hydroxy and alkyl).Specifically, R⁴ is piperidinyl, pyrrolidinyl, methylaminomethyl,1(R,S)-amino-ethyl, 1(R)-amino-ethyl, 1(S)-amino-ethyl,1(R,S)-(methylamino)-ethyl, 1(R)-(methylamino)-ethyl,1(S)-(methylamino)-ethyl, 1(R,S)-(dimethylamino)-ethyl,1(R)-(dimethylamino)-ethyl, 1(S)-(dimethylamino)-ethyl,1(R,S)-amino-propyl, 1(R)-amino-propyl, 1(S)-amino-propyl,I(R,S)-(methylamino)-propyl, 1(R)-(methylamino)-propyl,1(S)-(methylamino)-propyl, S(R,S)-(dimethylamino)-propyl,1(R)-(dimethylamino)-propyl, 1(S)-(dimethylamino)-propyl,1(R,S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl,1(R)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl, or1(S)-(3,4-cis-dihydroxy-cyclopentylamino)-ethyl.

Another embodiment of the Invention (E) is directed to a Compoundselected from Group A, Group B, and Group C where

Group A

-   A is phenylene optionally substituted with one or two groups    selected from R¹⁰, R¹², R¹⁴, and R¹⁶ where R¹⁰, R¹², R¹⁴ and R¹⁶ are    independently hydrogen or halo;-   X is halo;-   R¹, R², R⁵ and R⁶ are hydrogen;-   R³ is hydrogen, halo, hydroxy, alkoxy, or amino;-   R⁴ is hydrogen, —NR⁸R^(8′), —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),    —NR⁸C(O)R^(8′), —CH₂N(R²⁵)(NR^(25a)R^(25b)),    —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)),    —CH₂NR²⁵C(═NH)(N(R^(25a))(CN)), —CH₂NR²⁵C(═NH)(R²⁵),    —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, cycloalkyl,    heterocycloalkyl, or heteroaryl; where the R⁴ alkyl is optionally    substituted with one, two, or three groups independently selected    from —OR⁸, halo, nitro, —S(O)_(m)R⁹, optionally substituted    heterocycloalkyl, —NR⁸R^(8′), —NR⁸C(O)R^(8′), —NR⁸S(O)₂R⁹,    —NR⁸C(O)OR^(8′), and aryl; where the R⁴ cycloalkyl is optionally    substituted with one or two groups selected from —OR⁸ and    —NR⁸R^(8′); where the R⁴ heterocycloalkyl is optionally substituted    with one or two groups independently selected from alkyl and    —C(O)OR⁸; and where the R⁴ heteroaryl is optionally substituted with    —NR⁸R^(8′); or-   R³ and R⁴ together with the carbon to which they are attached form    C(O) or C(═NOH);-   m is 0;-   R⁷ is halo;-   R⁸ and R^(8′) are independently selected from hydrogen, hydroxy,    alkyl, alkenyl, alkynyl, aryl, heterocycloalkyl, heteroaryl, and    cycloalkyl;-   where the R⁸ and R^(8′) alkyl are independently optionally    substituted with one, two, or three groups independently selected    from hydroxy, —NR³⁰R^(30′) (where R³⁰ and R^(30′) are independently    hydrogen, alkyl, or hydroxyalkyl), optionally substituted    heteroaryl, optionally substituted cycloalkyl), optionally    substituted alkoxy, optionally substituted cycloalkyl, optionally    substituted aryl, optionally substituted heterocycloalkyl,    optionally substituted heteroaryl, —C(O)NR³³R^(33a) (where R³³ is    hydrogen or alkyl and R^(33a) is alkyl, alkenyl, alkynyl, or    cycloalkyl), optionally substituted aryloxy, —S(O)_(n)R³¹ (where n    is 0 and R³¹ is alkyl), carboxy, alkoxycarbonyl, and    —NR³²C(O)R^(32a) (where R³² is hydrogen or alkyl and R^(32a) is    alkyl, alkenyl, alkoxy, or cycloalkyl); or where the alkyl is    optionally substituted with one, two, three, four, or five halo;-   where the R⁸ and R^(8′) heteroaryl are independently optionally    substituted with one or two groups independently selected from amino    and alkyl;-   where the R⁸ and R^(8′) heterocycloalkyl are independently    optionally substituted with one, two, or three groups independently    selected from alkyl, alkoxycarbonyl, optionally substituted    arylalkyl, hydroxy, alkoxy, and hydroxyalkyl;-   where the R⁸ and R^(8′) aryl are independently optionally    substituted with one or two groups independently selected from    hydroxy, alkoxy, halo, —NR³²C(O)R^(32a) (where R³² is hydrogen or    alkyl and R^(32a) is alkyl, alkenyl, alkoxy, or cycloalkyl), and    —NR³⁴SO₂R^(34a) (where R³⁴ is hydrogen or alkyl and R^(34a) is    alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl);    and-   where the R⁸ and R^(8′) cycloalkyl are independently optionally    substituted with one, two, or three groups independently selected    from hydroxy, hydroxyalkyl, alkoxy, carboxy, —C(O)NR³³R^(33a) (where    R³³ is hydrogen or alkyl and R^(33a) is alkyl, alkenyl, alkynyl, or    cycloalkyl), and optionally substituted cycloalkyl; and-   R⁹ is alkyl or aryl;

Group B

-   A is thien-3,4-diyl, benzo[d]isoxazol-5,6-diyl, 1H-indazol-5,6-diyl    (optionally substituted at the N1 position with R¹⁹ where R¹⁹ is    alkyl or alkenyl), benzol[d]oxazol-5,6-diyl,    benzo[d]thiazol-5,6-diyl, 1H-benzo[d]imidazol-5,6-diyl (optionally    substituted at the N1 position with R¹⁹ where R¹⁹ is alkyl or    alkonyl), 1H-benzo[d][1,2,3]triazol-5,6-diyl (optionally substituted    at the N1 position with R¹⁹ where R¹⁹ is alkyl or alkenyl),    imidazo[1,2-a]pyridin-6,7-diyl, cinnolin-6,7-diyl,    quinolin-6,7-diyl, pyridin-3,4-diyl, or 1-oxido-pyridin-3,4-diyl;    where A is optionally substituted with one, two, or three groups    independently selected from R¹⁰, R¹², R¹⁴, R¹⁶ and R¹⁹ where R¹⁰,    R¹², R¹⁴ and R¹⁶ are independently hydrogen, alkyl, halo, or amino;    and R¹⁹ is hydrogen or alkyl;-   X is halo;-   R¹, R², R⁵ and R⁶ are hydrogen;-   R³ is hydrogen or hydroxy;-   R⁴ is —NR⁸R^(8′), heterocycloalkyl, heteroaryl, or alkyl; where the    alkyl is optionally substituted with —NR⁸R^(8′) and where the    heteroaryl is optionally substituted with alkyl;-   R⁷ is halo;-   R⁸ is hydrogen or alkyl; and-   R^(8′) is hydrogen, alkyl, or cycloalkyl; where the cycloalkyl is    optionally substituted with one or two groups independently selected    from hydroxy and alkyl;

Group C

-   A is

-   where R¹⁰ is hydrogen or halo;-   R^(10a) is hydrogen or alkyl;-   Y¹ is —CH— or ═N—;-   X is halo;-   R¹, R², R⁵ and R⁶ are hydrogen;-   R³ is hydrogen or hydroxy;-   R⁴ is —NR⁸R^(8′), heterocycloalkyl, heteroaryl, or alkyl; where the    alkyl is optionally substituted with —NR⁸R^(8′) and where the    heteroaryl is optionally substituted with alkyl;-   R⁷ is halo;-   R⁸ is hydrogen or alkyl; and-   R^(8′) is hydrogen, alkyl, or cycloalkyl; where the cycloalkyl is    optionally substituted with one or two groups independently selected    from hydroxy and alkyl.

One embodiment of the invention provides a pharmaceutical compositionwhich comprises a compound of Formula I selected from Group A, or apharmaceutically acceptable salt or solvate therof and apharmaceutically acceptable carrier, excipient, or diluent.

Another embodiment of the invention provides a pharmaceuticalcomposition which comprises a compound of Formula I selected from GroupB, or a pharmaceutically acceptable salt or solvate therof and apharmaceutically acceptable carrier, excipient, or diluent.Specifically, the compound is of Formula I(c), I(d), I(e), I(f), I(g),I(h), I(i), I(j), I(k), I(m), I(n), I(o), I(p), I(q), I(r), I(s), I(t),I(u), I(v), I(w), I(x), I(cc), or I(dd).

Another embodiment of the invention provides a pharmaceuticalcomposition which comprises a compound of Formula I selected from GroupC, or a pharmaceutically acceptable salt or solvate therof and apharmaceutically acceptable carrier, excipient, or diluent.

Another embodiment of the invention provides a pharmaceuticalcomposition which comprises a compound of Formula I selected from GroupD, or a pharmaceutically acceptable salt or solvate therof and apharmaceutically acceptable carrier, excipient, or diluent. In anotherembodiment, the invention comprises a method of inhibiting MEK in acell, comprising contacting a cell with a compound of Formula I selectedfrom Group A or a pharmaceutically acceptable salt or solvate therof, orwith a pharmaceutical composition comprising a therapeutically effectiveamount of a compound of Formula I selected from Group A and apharmaceutically acceptable carrier, excipient, or diluent.

In another embodiment, the invention comprises a method of inhibitingMEK in a cell, comprising contacting a cell with a compound of Formula Iselected from Group B or a pharmaceutically acceptable salt or solvatetherof, or with a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula I selectedfrom Group B and a pharmaceutically acceptable carrier, excipient, ordiluent.

In another embodiment, the invention comprises a method of inhibitingMEK in a cell, comprising contacting a cell with a compound of Formula Iselected from Group C or a pharmaceutically acceptable salt or solvatetherof, or with a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula I selectedfrom Group C and a pharmaceutically acceptable carrier, excipient, ordiluent.

In another embodiment, the invention comprises a method of inhibitingMEK in a cell, comprising contacting a cell with a compound of Formula Iselected from Group D or a pharmaceutically acceptable salt or solvatetherof, or with a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula I selectedfrom Group D and a pharmaceutically acceptable carrier, excipient, ordiluent.

Another embodiment of the Invention provides a method for treating aproliferative disease which method comprises administering to a patienta compound of Formula I or a pharmaceutically acceptable salt or solvatetherof, or administering a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula I and apharmaceutically acceptable carrier, excipient, or diluent. In aspecific embodiment, the disease is cancer. More specifically, thecancer is selected from malignant melanoma, colorectal cancer,pancreatic cancer, breast cancer, non-small cell lung cancer, small celllung cancer, papillary and anaplastic thyroid cancer, and endometriodovarian cancers.

J One of ordinary skill in the art would understand that certaincrystallized, protein-ligand complexes and their corresponding x-raystructure coordinates can be used to reveal new structural informationuseful for understanding the biological activity of kinases as describedherein. As well, the key structural features of the aforementionedproteins, particularly, the shape of the ligand binding site, are usefulin methods for designing or identifying selective modulators of kinasesand in solving the structures of other proteins with similar features.Such protein-ligand complexes, having compounds of the invention astheir ligand component, are an aspect of the invention.

As well, one of ordinary skill in the art would appreciate that suchsuitable x-ray quality crystals can be used as part of a method ofidentifying a candidate agent capable of binding to and modulating theactivity of kinases. Such methods may be characterized by the followingaspects: a) introducing into a suitable computer program, informationdefining a ligand binding domain of a kinase in a conformation (e.g. asdefined by x-ray structure coordinates obtained from suitable x-rayquality crystals as described above) wherein the computer programcreates a model of the three dimensional structures of the ligandbinding domain, b) introducing a model of the three dimensionalstructure of a candidate agent in the computer program, c) superimposingthe model of the candidate agent on the model of the ligand bindingdomain, and d) assessing whether the candidate agent model fitsspatially into the ligand binding domain. Aspects a-d are notnecessarily carried out in the aforementioned order. Such methods mayfurther entail: performing rational drug design with the model of thethree-dimensional structure, and selecting a potential candidate agentin conjunction with computer modeling.

Additionally, one skilled in the art would appreciate that such methodsmay further entail: employing a candidate agent, so-determined to fitspatially into the ligand binding domain, in a biological activity assayfor kinase modulation, and determining whether said candidate agentmodulates kinase activity in the assay. Such methods may also includeadministering the candidate agent, determined to modulate kinaseactivity, to a mammal suffering from a condition treatable by kinasemodulation, such as those described above.

Also, one skilled in the art would appreciate that compounds of theinvention can be used in a method of evaluating the ability of a testagent to associate with a molecule or molecular complex comprising aligand binding domain of a kinase. Such a method may be characterized bythe following aspects: a) creating a computer model of a kinase bindingpocket using structure coordinates obtained from suitable x-ray qualitycrystals of the kinase, b) employing computational algorithms to performa fitting operation between the test agent and the computer model of thebinding pocket, and c) analyzing the results of the fitting operation toquantify the association between the test agent and the computer modelof the binding pocket.

Representative Compounds

Representative compounds of Formula I are depicted below. The examplesare merely illustrative and do not limit the scope of the invention inany way. Compounds of the invention are named according to systematicapplication of the nomenclature rules agreed upon by the InternationalUnion of Pure and Applied Chemistry (IUPAC), International Union ofBiochemistry and Molecular Biology (IUBMB), and the Chemical AbstractsService (CAS). Names were generated using ACD/Labs naming software 8.00release, product version 8.08.

TABLE 1 Cmpd No. Structure Name  1

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}-carbonyl)azetidin-3-ol  2

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-one  3

6-(azetidin-1-ylcarbonyl)-2,3- difluoro-N-(2-fluoro-4-iodophenyl)aniline  4

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(hydroxymethyl)azetidin-3-ol  5

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(trifluoromethyl)azetidin-3-ol  6

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-prop-2-en-1-ylazetidin-3-ol  7

3-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]propane- 1,2-diol  8

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-ethylazetidin-3-ol  9

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-methylazetidin-3-ol 10

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-ethenylazetidin-3-ol 11

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-one oxime 12

[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]methanol 13

1-[1-({3,4-difIuoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethane-1,2- diol 14

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine 15

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N-hydroxyazetidine-3-carboxamide 16

1,1-dimethylethyl [1-({3,4-difluoro- 2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-yl]carbamate 17

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(pyrrolidin-1-ylmethyl)azetidin- 3-ol 18

3-[(diethylamino)methyl]-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 19

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(dimethylamino)methyl]azetidin- 3-ol 20

N-butyl-1-({3,4-difluoro-2-[(2- fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidine-3-carboxamide 21

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N-prop-2-en-1-ylazetidine-3- carboxamide 22

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-2-methylpropanamide 23

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]formamide 24

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-3,4- dihydroxybutanamide 25

methyl [1-({3,4-difluoro-2-[(2- fluoro-4-iodophonyl)amino]phenyl}carbonyl) azetidin-3-yl]carbamate 26

N-butyl-1-({3,4-difluoro-2-[(2- fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-amine 27

1-({4-[(2-fluoro-4- iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-amine 28

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol 29

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol 30

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-pyrrolidin-2-ylazetidin-3-ol 31

(R)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-pyrrolidin-2-ylazetidin-3-ol 32

(S)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-pyrrolidin-2-ylazetidin-3-ol 33

3-(aminomethyl)-1-({3,4-difluoro-2- [(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 34

3-[(1S)-1-aminoethyl]-1-({3,4-difluoro- 2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 35

3-[(1R)-1-aminoethyl]-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 36

(3-(1-aminopropyl)-3-hydroxyazetidin- 1-yl)(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)methanone 37

(R)-(3-(1-aminopropyl)-3- hydroxyazetidin-1-yl)(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)phenyl)methanone 38

(S)-(3-(1-aminophenyl)-3- hydroxyazetidin-1-yl)(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)phenyl)methanone 39

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N-ethylazetidine-3-carboxamide 40

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N-(2-hydroxyethyl)azetidin-3- carboxamide 41

1-({3,4-difiuoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N-(2-piperidin-1-ylethyl)azetidine-3- carboxamide 42

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N-phenylazetidine-3-carboxamide 43

N-[2-(diethylamino)ethyl]-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidine-3-carboxamide 44

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(morpholin-4-ylmethyl)azetidin-3-ol 45

1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}piperidin- 4-ol 46

3-{[bis(2- hydroxyethyl)amino]methyl}-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 47

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-2-(4-methylpiperazin-1- yl)acetamide 48

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(4-methylpiperazin-1- yl)methyl]azetidin-3-ol 49

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(4-methyl-1,4-diazepan-1- yl)methyl]azetidin-3-ol 50

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[methyl(1-methylpyrrolidin-3- yl)amino]methyl}azetidin-3-ol 51

3-(1,4′-bipiperidin-1′-ylmethyl)-1- ({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 52

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N,N-bis(2- hydroxyethyl)glycinamide 53

3-({4-[2-(diethylamino)ethyl]piperazin-1-yl}methyl)-1-({3,4-difluoro-2-[(2- fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 54

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2- hydroxyethyl)(methyl)amino]methyl} azetidin-3-ol 55

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-2-piperidin-1-ylacetamide 56

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N3-(2-hydroxyethyl)-N3- methyl-beta-alaninamide 57

N-[1-({3,4 difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N3,N3-bis(2- hydroxyethyl)-beta-alaninamide 58

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N2,N2-diethylglycinamide 59

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N-methylazetidin-3-amine 60

1-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N,N-dimethylpyrrolidin-3- amine 61

2-{[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]amino}ethanol 62

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]propane-1,3-diamine 63

3-[(dimethylamino)methyl]-1-({4-[(2- fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-ol 64

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N-methyl-N-(2-pyridin-2- ylethyl)azetidin-3-amine 65

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N2-methylglycinamide 66

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N-ethylazetidin-3-amine 67

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N-(2-methylpropyl)azetidin-3-amine 68

N-(cyclopropylmethyl)-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-amine 69

N-(cyclohexylmethyl)-1-({3,4-difluoro- 2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-amine 70

N-(cyclopentylmethyl)-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-amine 71

3-(azetidin-1-ylmethyl)-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 72

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N-[(2,3- dihydroxypropyl)oxy]azetidine-3- carboxamide 73

2-({[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-2-yl]methyl}amino)ethanol 74

N-{[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-2-yl]methyl}ethane-1,2-diamine 75

N-[1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]glycinamide 76

6-({3- [(dimethylamino)methyl]azetidin-1- yl}carbonyl)-2,3-difluoro-N-(2fluoro- 4-iodophenyl)aniline 77

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(1- methylethyl)amino]methyl}azetidin-3- ol 78

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N-(3,4-dihydroxybutyl)azetidine-3- carboxamide 79

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N-(2,3-dihydroxypropyl)azetidine-3- carboxamide 80

1-({2,4-difluoro-6-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine 81

1-({4,5-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine 82

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidine-3-carboxamide 83

6-{[3-(aminomethyl)-3- (methyloxy)azetidin-1-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4- iodophenyl)aniline 84

N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}acetamide 85

2,3-difluoro-N-(2-fluoro-4- iodophenyl)-6-[(3-{[(1-methylethyl)amino]methyl}azetidin-1- yl)carbonyl]aniline 86

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(ethylamino)methyl]azetidin-3-ol 87

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{2-[(1- methylethyl)amino]ethyl}azetidin-3-ol 88

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(2-hydroxy-1,1-dimethylethyl)azetidin- 3-ol 89

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{1,1-dimethyl-2-[(1- methylethyl)amino]ethyl}azetidin-3-ol 90

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(1- methylethyl)amino]methyl}azetidin-3- amine 91

3-[(cyclopropylamino)methyl]-1- ({3,4-difIuoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 92

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2,2,2- trifluoroethyl)amino]methyl}azetidin- 3-ol 93

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(1H-imidazol-1-ylmethyl)azetidin-3-ol 94

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(1,1- dimethylethyl)amino]methyl}-azetidin- 3-ol 95

3-[(cyclopentylamino)methyl]-1- ({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 96

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-hydroxy-N-prop-2-en-1-ylazetidine-3- carboxamide 97

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-N-(2,3-dihydroxypropyl)-3- hydroxyazetidine-3-carboxamide 98

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(1H-1,2,3-triazol-1-ylmethyl)azetidin- 3-ol 99

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2,2- dimethylpropyl)amino]methyl}azetidin- 3-ol 100

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(propylamino)methyl]azetidin-3-ol 101

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2- methylpropyl)amino]methyl} azetidin-3-ol 102

3-{[(cyclopropylmethyl)amino] methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 103

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(phenylmethyl)amino]methyl} azetidin-3-ol 104

3-{[(cyclohexylmethyl)amino]methyl}- 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 105

3-[(butylamino)methyl]-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 106

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[(1-ethylpyrrolidin-2- yl)methyl]amino}methyl)azetidin-3-ol 107

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2- hydroxyethyl)amino]methyl}azetidin- 3-ol 108

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[2- (dimethylamino)ethyl]amino}methyl) azetidin-3-ol 109

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxy-1,1- dimethylethyl)amino]methyl}azetidin- 3-ol 110

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[2-(4- methylphenyl)ethyl]amino}methyl) azetidin-3-ol 111

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(prop-2-en-1-ylamino)methyl]azetidin- 3-ol 112

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[2-(1-methylpyrrolidin-2- yl)ethyl]amino}methyl)azetidin-3-ol 113

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(2,3-dihydro-1H-inden-2- ylamino)methyl]azetidin-3-ol 114

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(tetrahydrofuran-2- ylmethyl)amino]methyl}azetidin-3-ol 115

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[2-(tetrahydro-2H-pyran-4- yl)ethyl]amino}methyl)azetidin-3-ol 116

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[(1S,2S)-2- hydroxycyclopentyl]amino}methyl) azetidin-3-ol 117

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(1,1-dimethylprop-2-yn-1- yl)amino]methyl}azetidin-3-ol 118

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(3-pyrrolidin-1- ylpropyl)amino]methyl}azetidin-3-ol 119

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(1,2- dimethylpropyl)amino]methyl}azetidin- 3-ol 120

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[2-(1H-imidazol-4- yl)ethyl]amino}methyl)azetidin-3-ol 121

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[1-methyl-2- (methyloxy)ethyl]amino}methyl) azetidin-3-ol 122

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[3- (ethyloxy)propyl]amino}methyl) azetidin-3-ol 123

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(1- ethylpropyl)amino]methyl}azetidin-3- ol 124

1-({3,4-difluoro-2-[(2-fluoro-4- |iodophenyl)amino]phenyl}carbonyl)-3-{[(3,3- dimethylbutyl)amino]methyl}azetidin- 3-ol 125

ethyl 4-({[1-({3,4-difluoro-2-[(2- fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}amino)piperidine-1- carboxylate 126

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(3- methylbutyl)amino]methyl}azetidin-3- ol 127

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[2- (ethyloxy)ethyl]amino}methyl)azetidin- 3-ol 128

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[3- (dimethylaraino)propyl]amino}methyl) azetidin-3-ol 129

3-[(cyclobutylamino)methyl]-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 130

3-({[3- (diethylamino)propyl]amino}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol 131

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[3-(1H-imidazol-1- yl)propyl]amino}methyl)azetidin-3-ol 132

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[2- (methylthio)ethyl]amino}methyl) azetidin-3-ol 133

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3({[1-(phenylmethyl)piperidin-4- yl]amino}methyl)azetidin-3-ol 134

3-({[2,2- bis(methyloxy)ethyl]amino}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol 135

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbanyl)-3-{[(1,1,3,3- tetramethylbutyl)amino]methyl} azetidin-3-ol 136

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(1,1- dimethylpropyl)amino]methyl} azetidin-3-ol 137

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(2,3-difluoro-1H-inden-1- ylamino)methyl]azetidin-3-ol 138

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[({2- [(phenylmethyl)oxy]cyclopentyl}amino) methyl]azetidin-3-ol 139

3-{[(3-amino-2- hydroxypropyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol140

1-({3,4-difluoro-2-[(2-fluoro-4- iiodophenyl)amino]phenyl}carbonyl)-3-({[2-hydroxy-1- (phenylmethyl)ethyl]amino}methyl) azetidin-3-ol 141

3-[(cyclooctylamino)methyl]-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 142

3-{[(1-cyclohexylethyl)amino]methyl}- 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 143

3-[(cycloheptylamino)methyl]-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 144

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2-pyridin-3- ylethyl)amino]methyl}azetidin-3-ol 145

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[3- (methylthio)propyl]amino}methyl) azetidin-3-ol 146

N-cyclohexyl-N~2~-{[1-({3,4-difluoro- 2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}-2-methylalaninamide 147

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(tetrahydro-2H-pyran-4- ylmethyl)amino]methyl}azetidin-3-ol 148

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(3- hydroxypropyl)amino]methyl} azetidin-3-ol 149

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2-pyridin-4- ylethyl)amino]methyl}azetidin-3-ol 150

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[1-(phenylmethyl)pyrrolidin-3- yl]amino}methyl)azetidin-3-ol 151

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[2-(2- thienyl)ethyl]amino}methyl)azetidin-3- ol 152

3-[({2-[bis(1- methylethyl)amino]ethyl}amino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 153

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[2- (phenyloxy)ethyl]amino}methyl) azetidin-3-ol 154

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(phenylamino)methyl]azetidin-3-ol 155

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2- hydroxypropyl)amino]methyl}azetidin- 3-ol 156

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[({2-[(1- methylethyl)oxy]ethyl}amino)methyl] azetidin-3-ol 157

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(1-ethylpiperidin-3- yl)amino]methyl}azetidin-3-ol 158

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[2- (methyloxy)ethyl]amino}methyl) azetidin-3-ol 159

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(1-nitropropyl)azetidin-3-ol 160

3-(1-aminoethyl)-1-({3,4-difluoro-2- [(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 161

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[(1-methylpiperidin-4- yl)methyl]amino}methyl)azetidin-3-ol 162

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[4- (dimethylamino)butyl]amino}methyl) azetidin-3-ol 163

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2-furan-2- ylethyl)amino]methyl}azetidin-3-ol 164

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{1-[(1,1- dimethylethyl)amino]ethyl}azetidin-3- ol 165

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2-ethylbutyl)amino]methyl}azetidin- 3-ol 166

1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}pyrrolidin-3-ol 167

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({(2S)-2- [(methyloxy)methyl]pyrrolidin-1- yl}methyl)azetidin-3-ol 168

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2- hydroxyphenyl)amino]methyl}azetidin- 3-ol 169

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(4- hydroxyphenyl)amino]methyl}azetidin- 3-ol 170

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(3- hydroxyphenyl)amino]methyl}azetidin- 3-ol 171

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(phenyloxy)methyl]azetidin-3-ol 172

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(1r,3r,5R,7R)- tricyclo[3.3.1.1~3,7~]dec-2-ylamino]methyl}azetidin-3-ol 173

3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}amino)propane-1,2-diol 174

N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}-L-alanine 175

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(phenylthio)methyl]azetidin-3-ol 176

N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}-D-alanine 177

methyl N-{[1-({3,4-difluoro-2-[(2- fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}alaninate 178

3-[({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}amino)oxy]propane-1,2-diol 179

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[(5-methyl-1,3,4-oxadiazol-2- yl)methyl]amino}methyl)azetidin-3-ol 180

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(1- methylbutyl)amino]methyl}azetidin-3- ol 181

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(1- methylpropyl)amino]methyl}azetidin- 3-ol 182

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2- methylbutyl)amino]methyl}azetidin-3- o! 183

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(pentylamino)methyl]azetidin-3-ol 184

3-[(1S)-1-aminoethyl]-1-({8-fluoro- 7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2- a]pyridin-6-yl}carbonyl)azetidin-3- ol 185

1-({8-fluoro-7-[(2-fluoro-4- iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-[(1S)-1- (methylamino)ethyl]azetidin-3-ol 186

3-[(cyclohexylamino)methyl]-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 187

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[1-(ethylamino)ethyl]azetidin-3-ol 188

3-[(azepan-3-ylamino)methyl]-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 189

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[2-(dimethylamino)-1- methylethyl]amino}methyl)azetidin-3- ol 190

N-cyclopropyl-1-({[1-({3,4-difluoro-2- [(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}amino)cyclopentane- carboxamide 191

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[2-(2,3-dihydro-1H-indol-3- yl)ethyl]amino}methyl)azetidin-3-ol 192

N~2~-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)- 3-hydroxyazetidin-3-yl]methyl}-N-ethyl-2-methylalaninamide 193

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(2-methylhydrazino)methyl]azetidin- 3-ol 194

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(hydroxyamino)methyl]azetidin-3-ol 195

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(methyloxy)amino]methyl}azetidin- 3-ol 196

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(ethyloxy)amino]methyl}azetidin-3- ol 197

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[1-(ethylamino)propyl]azetidin-3-ol 198

3-[(azetidin-3-ylamino)methyl]-1- ({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 199

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(1,3-thiazol-2- ylamino)methyl]azetidin-3-ol 200

3-(1H-benzimidazol-2-yl)-1-({8- fluoro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2- a]pyridin-6-yl}carbonyl)azetidin-3- ol 201

3-(1H-benzimidazol-2-yl)-1-({7-[(4- bromo-2-fluorophenyl)amino]-8-fluoroimidazo[1,2-a]pyridin-6- yl}carbonyl)azetidin-3-ol 202

1,1-dimethylethyl [3-({[1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}amino)propyl]carbamate 203

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(pyrrolidin-2- ylmethyl)amino]methyl}azetidin-3-ol 204

1,1-dimethylethyl 4-[({[1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}amino)methyl]piperidine-1- carboxylate 205

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[(2- hydroxyphenyl)methyl]amino}methyl) azetidin-3-ol 206

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[(3- hydroxyphenyl)methyl]amino}methyl) azetidin-3-ol 207

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[(4- hydroxyphenyl)methyl]amino}methyl) azetidin-3-ol 208

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(4- hydroxybutyl)amino]methyl}azetidin- 3-ol 209

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2- hydroxyethyl)oxy]methyl}azetidin-3-ol 210

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[(1S,2S)-2- hydroxycyclohexyl]amino}methyl) azetidin-3-ol 211

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3{[(1,1-dimehyl-2-pyrrolidin-1- ylethyl)amino]methyl}azetidin-3-ol 212

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[(1-methyl-1H-imidazol-4- yl)methyl]amino}methyl)azetidin-3-ol 213

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[(1-methyl-1H-imidazol-5- yl)methyl]amino}methyl)azetidin-3-ol 214

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[(2S)-2- (methyloxy)cyclopenlyl]amino}methyl) azetidin-3-ol 215

3-{[1,1′-bi(cyclohexyl)-2- ylamino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 216

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[3- (methyloxy)phenyl]amino}methyl) azetidin-3-ol 217

1-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}amino)cyclopentanecarboxylic acid 218

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(4- fluorophenyl)amino]methyl}azelidin-3- ol 219

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(1,3,5-triazin-2- ylamino)methyl]azetidin-3-ol 220

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(trans-4- hydroxycyclohexyl)amino]methyl} azetidin-3-ol 221

3-[(cyclopent-3-en-1-ylamino)methyl]- 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 222

N-[4-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)- 3-hydroxyazetidin-3-yl]methyl}amino)phenyl]acetamide 223

N-[3-({[3-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)- 3-hydroxyazetidin-3-yl]methyl}amino)phenyl]acctamide 224

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(1-methylpyrrolidin-2-yl)azetidin-3-ol 225

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(1H-1,2,4-triazol-3- ylamino)methyl]azetidin-3-ol 226

3-[1-(diethylamino)propyl]-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 227

3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}amino)-5-(hydroxymethyl)cyclopentane-1,2- diol 228

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-piperidin-2-ylazetidin-3-ol 229

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(3- fluorophenyl)amino]methyl}azetidin-3- ol 230

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(1-methylpiperidin-2-yl)azetidin-3-ol 231

1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}guanidine 232

1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}-3-nitroguanidine 233

N-{1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}acetamide 234

(2R)-N-{1-[1-({3,4-difluoro-2-[(2- fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]ethyl}-3,3,3-trifluoro-2-(methyloxy)-2- phenylpropanamide 235

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(piperidin-4- ylmethyl)amino]methyl}azetidin-3-o1 236

3-{[(3-aminopropyl)amino]methyl}-1- ({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 237

1-({3,4-difluoro-2-[(2-fluoro-4- ioduphenyl)amino]phenyl}carbonyl)-3-[({[2-(4-methylpiperazin-1- yl)phenyl]methyl}amino)methyl] azetidin-3-ol238

3-{[(1,1-dimethylethyl)amino]methyl}-1-({4-[(2-fluoro-4-iodophenyl)amino]- 3-thienyl}carbonyl)azetidin-3-ol239

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2- hydroxycyclohexyl)amino]methyl} azetidin-3-ol 240

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2,2,3,3,3- pentafluoropropyl)amino]methyl} azetidin-3-ol 241

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(3,3,3- trifluoropropyl)amino]methyl}azetidin- 3-ol 242

N-[3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)- 3-hydroxyazetidin-3-yl]methyl}amino)phenyl] methanesulfonamide 243

N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}methanesulfonamide 244

3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}amino)-1H-pyrazol-5-ol 245

(1R,2S)-4-({[1-({3,4-difluoro-2-[(2- fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}amino)cyclopentane-1,2-diol 246

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[1-(hydroxymethyl)cyclohexyl]amino} methyl)azetidin-3-ol 247

3-{[(3-chlorophenyl)amino]methyl}-1- ({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 248

3-{[(4-chlorophenyl)amino]methyl}-1- ({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 249

3-[(5-amino-3-methyl-1H-pyrazol-1- yl)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 250

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(5-methyl-1H-pyrazol-3- yl)amino]methyl}azetidin-3-ol 251

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(1-ethylpyrrolidin-2-yl)azetidin-3-ol 252

(2R)-N-{(1S)-1-[1-({3,4-difluoro-2-[(2- fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]ethyl}-3,3,3-trifluoro-2-(methyloxy)-2- phenylpropanamide 253

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[4- (methyloxy)phenyl]amino}methyl) azetidin-3-ol 254

3-(1-amino-2-methylpropyl)-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 255

3-{[(4-aminophenyl)amino]methyl}-1- ({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 256

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxy-2- methylcyclopentyl)amino]methyl} azetidin-3-ol 257

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{1-[(4- hydroxycyclohexyl)amino]ethyl} azetidin-3-ol 258

methyl (2xi)-2-deoxy-2-({[1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]methyl}amino)-beta-D-arabino-hexopyranoside 259

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-pyridin-2-ylazetidin-3-ol 260

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-({[1- (hydroxymethyl)cyclopentyl]amino} methyl)azetidin-3-ol 261

1-cyano-3-{[1-({3,4-difluoro-2-[(2- fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}guanidine 262

6-({3-[(ethylamino)methyl]-3- fluoroazetidin-1-yl}carbonyl)-2,3-difluoro-N-(2-fluoro-4- iodophenyl)aniline 263

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(1-nitroethyl)azetidin-3-ol 264

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(3-fluoro-4- hydroxyphenyl)amino]methyl}azetidin- 3-ol 265

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-{[(2-fluoro-4- hydroxyphenyl)amino]methyl}azetidin- 3-ol 266

3-(1-aminoethyl)-1-({8-chloro-7-[(2- fluoro-4-iodophenyl)amino]imidazo[1,2- a]pyridin-6-yl}carbonyl)azetidin-3-ol 267

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[1-(methylamino)ethyl]azetidin-3-ol 268

1-({8-fluoro-7-[(2-fluoro-4- iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-[(2S)- piperidin-2-yl]azetidin-3-ol 269

1-({8-fluoro-7-[(2-fluoro-4- iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-{(1S)-1- [(2-hydroxy-2-methylcyclopentyl)amino]ethyl} azetidin-3-ol 270

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(1H-imidazol-2-yl)azetidin-3-ol 271

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(1H-pyrrol-2-yl)azetidin-3-ol 272

N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydraxyazetidin-3yl]methyl}benzenecarboximidamide 273

3-({[(E)-1-amino-2- nitroethenyl]amino}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol274

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(1-methyl-1-nitroethyl)azetidin-3-ol 275

3-(1-amino-1-methylethyl)-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 276

3-[(1H-benzimidazol-2- ylamino)methyl]-1-({3,4-difluoro-2- [(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 277

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(1H-imidazol-2- ylamino)methyl]azetidin-3-ol 278

methyl {1-[1-({3,4-difluoro-2-[(2- fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate 279

3-(1H-benzimidazol-2-yl)-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 280

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[1-(dimethylamino)ethyl]azetidin-3-ol 281

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(pyrimidin-2-ylamino)methyl]azetidin- 3-ol 282

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(pyridin-2-ylamino)methyl]azetidin-3 ol 283

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(1-methyl-1H-imidazol-2-yl)azetidin-3- ol 284

3-(1-aminobutyl)-1-({3,4-difluoro-2- [(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 285

1-({2-fluoro-3-[(2-fluoro-4- iodophenyl)amino]pyridin-4-yl}carbonyl)-3-[(2S)-pyrrolidin-2- yl]azetidin-3-ol 286

1-({8-fluoro-7-[(2-fluoro-4- iodophenyl)amino]-4-methylcinnolin-6-yl}carbonyl)-3- [(2S)-piperidin-2-yl]azetidin-3-ol 287

3-[amino(phenyl)methyl]-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 288

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(5-methyl-1H-imidazol-2-yl)azetidin-3- ol 289

1,1-dimethylethyl (2S)-2-[1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- hydroxyazetidin-3-yl]piperidine-1-carboxylate 290

1-({2-[(4-bromo-2- chlorophenyl)amino]-3,4-difluorophenyl}carbonyl)-3-piperidin- 2-ylazetidin-3-ol 291

3-(1-amino-3-hydroxypropyl)-1-({3,4- difluoro-2-[(2-fluoro-4-iodophcnyl)amino]phenyl}carbonyl) azetidin-3-ol 292

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(1H-imidazol-2-ylmethyl)azetidin-3-ol 293

3-(1-aminocyclopentyl)-1-({3,4- difluoro-2-[(2-fluoro-4-iodophonyl)amino]phenyl}carbonyl) azetidin-3-ol 294

3-(2-aminocyclohexyl)-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 295

3-(2-aminocyclopentyl)-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)- azetidin-3-ol 296

1-({4-fluoro-5-[(2-fluoro-4- iodophenyl)amino]-1-methyl-1H-benzimidazol-6-yl}carbonyl)-3- piperidin-2-ylazetidin-3-ol 297

1-({5-[(4-bromo-2- chlorophenyl)amino]-4-fluoro-1-methyl-1H-benzimidazol-6- yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol 298

1-({8-chloro-7-[(2-fluoro-4- iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-piperidin-2- ylazetidin-3-ol 299

1-({2-[(4-bromo-2- fluorophenyl)amino]-3,4-difluorophenyl}carbomyl)-3-piperidin- 2-ylazetidin-3-ol 300

1-({7-[(4-bromo-2- fluorophenyl)amino]-8- fluoroimidazo[1,2-a]pyridin-6-yl}carbonyl)-3-[(2S)-piperidin-2- yl]azetidin-3-ol 301

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(3-methyl-1-nitrobutyl)azetidin-3-ol 302

3-(2-aminopyrimidin-4-yl)-1-({3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl) azetidin-3-ol 303

1-({7-[(4-bromo-2- chlorophenyl)amino]-8- chloroimidazo[1,2-a]pyridin-6-yl}carbonyl)-3-piperidin-2-ylazetidin- 3-ol 304

1-({8-chloro-7-[(2-fluoro-4- iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-[(2S)- piperidin-2-yl]azetidin-3-ol 305

1-({7-[(4-bromo-2- chlorophenyl)amino]-8- chloroimidazo[1,2-a]pyridin-6-yl}carbonyl)-3-[(2S)-piperidin-2- yl]azetidin-3-ol 306

1-({4-fluoro-5-[(2-fluoro-4- iodophenyl)amino]-1-methyl-1H-benzimidazol-6-yl}carbonyl)-3- [(2S)-piperidin-2-yl]azetidin-3-ol 307

3-[(1S)-1-aminoethyl]-1-({5-[(4- bromo-2-chlorophenyl)amino]-4-fluoro-1-methyl-1H-benzimidazol-6- yl}carbonyl)azetidin-3-ol 308

1-({5-[(4-bromo-2- chlorophenyl)amino]-4-fluoro-1-methyl-1H-benzimidazol-6- yl}carbonyl)-3-[(1S)-1-(methylamino)ethyl]azetidin-3-ol 309

4-[(4-bromo-2-fluorophenyl)amino]- 3-fluoro-5-({3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1- yl}carbonyl)pyridin-2(1H)-one 310

4-[(2-fluoro-4-iodophenyl)amino]-5- ({3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}carbonyl)-1- methylpyridin-2(1H)-one 311

4-[(2-fluoro-4-iodophenyl)amino]-5- ({3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}carbonyl)-1- methylpyridin-2(1H)-one 312

(±)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(trans)-2-hydroxycyclohexyl]azetidin- 3-ol

313

(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)phenyl)(3-hydroxy-3-((1S,2S)-2- hydroxycyclohexyl)azetidin-1- yl)methanone 314

(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)phenyl)(3-hydroxy-3-((1S,2R)-2- hydroxycyclohexyl)azetidin-1- yl)methanone 315

4-[(2-fluoro-4-iodophenyl)amino]-5- ({3-hydroxy-3-[(1S)-1-(methylamino)propyl]azetidin-1- yl}carbonyl)-1-methylpyridin- 2(1H)-one316

(±)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(cis)-2-hydroxycyclohexyl]azetidin-3- ol

317

(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)phenyl)(3-hydroxy-3-((1S,2R)-2- hydroxycyclohexyl)azetidin-1- yl)methanone 318

(3,4-difluoro-2-(2-fluoro-4- iodophenylamino)phenyl)(3-hydroxy-3-((1R,2S)-2- hydroxycyclohexyl)azetidin-1- yl)methanone 319

5-({3-[(1S)-1- (dimethylamino)ethyl]-3-hydroxyazetidin-1-yl}carbonyl)-4- [(2-fluoro-4-iodophenyl)amino]-1-methylpyridin-2(1H)-one 320

4-[(2-fluoro-4-iodophenyl)amino]-5- ({3-hydroxy-3-[(methylamino)methyl]azetidin-1- yl}carbonyl)-1-methylpyridin- 2(1H)-one321

5-{[3-(1H-benzimidazol-2-yl)-3- hydroxyazetidin-1-yl]carbonyl}-4-[(4-bromo-2-fluorophenyl)amino]-1- methylpyridin-2(1H)-one 322

4-[(4-bromo-2-fluorophenyl)amino]- 5-{[3-hydroxy-3-(1-methyl-1H-benzimidazol-2-yl)azetidin-1- yl]carbonyl}-1-methylpyridin- 2(1H)-one323

4-[(4-bromo-2-fluorophenyl)amino]- 5-({3-hydroxy-3-[(2S)-pyrrolidin-2-yl]azetidin-1-yl}carbonyl)-1- methylpyridin-2(1H)-one 324

1-({3-fluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol 325

1-({4-fluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol 326

1-({6-[(4-bromo-2- chlorophenyl)amino]-7-fluoro-3-methyl-1,2-benzisoxazol-5- yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol 327

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-(6-methylpiperidin-2-yl)azetidin- 3-ol 328

1-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-piperazin-2-ylazetidin-3-ol 329

5-[(2-fluoro-4-iodophenyl)amino]-6- ({3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}carbonyl)-2- methylpyridazin-3(2H)-one 330

5-[(4-bromo-2- chlorophenyl)amino]-6-({3- hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}carbonyl)-2- methylpyridazin-3(2H)-one 331

5-[(4-bromo-2- chlorophenyl)amino]-4-fluoro-6-({3-hydroxy-3-[(2S)-pyrrolidin-2- yl]azetidin-1-yl}carbonyl)-2-methylpyridazin-3(2H)-one 332

5-[(4-bromo-2- chlorophenyl)amino]-4-fluoro-6-({3-hydroxy-3-[(2R)-pyrrolidin-2- yl]azetidin-1-yl}carbonyl)-2-methylpyridazin-3(2H)-one 333

6-({3-[(1S)-1-aminoethyl]-3- hydroxyazetidin-1-yl}carbonyl)-5-[(2-fluoro-4-iodophenyl)amino]-2- methylpyridazin-3(2H)-one 334

6-({3-[(1S)-1-aminoethyl]-3- hydroxyazetidin-1-yl}carbonyl)-5-[(4-bromo-2-chlorophenyl)amino]- 2-methylpyridazin-3(2H)-one 335

5-[(4-bromo-2- chlorophenyl)amino]-6-{[3-((1S)-1- {[(3R,4S)-3,4-dihydroxycyclopentyl]amino}ethyl)- 3-hydroxyazetidin-1-yl]carbonyl}-2-methylpyridazin-3(2H)-one 336

5-[(4-bromo-2-fluorophenyl)amino]- 6-[(3-hydroxy-3-{(1S)-1-[(2-hydroxy-2- methylcyclopentyl)amino]propyl} azetidin-1-yl)carbonyl]-2-methylpyridazin-3(2H)-one 337

6-({3-[(1S)-1-aminopropyl]-3- hydroxyazetidin-1-yl}carbonyl)-5-[(4-bromo-2-fluorophenyl)amino]-2- methylpyridazin-3(2H)-one 338

6-{[3-(1H-benzimidaxol-2-yl)-3- hydroxyazetidin-1-yl]carbonyl}-5-[(2-fluoro-4-iodophenyl)amino]-2- methylpyridazin-3(2H)-one 339

5-[(2-fluoro-4-iodophenyl)amino]-6- {[3-hydroxy-3-(1-methyl-1H-benzimidazol-2-yl)azetidin-1- yl]carbonyl}-2-methylpyridazin- 3(2H)-one340

1-({2-fluoro-3-[(2-fluoro-4- iodophenyl)amino]pyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2- yl]azetidin-3-ol 341

1-({3-[(2-fluoro-4- iodophenyl)amino]pyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2- yl]azetidin-3-ol 342

1-({3-[(2-fluoro-4- iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2- yl]azetidin-3-ol 343

1-({2-fluoro-3-[(2-fluoro-4- bromophenyl)amino]pyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2- yl]azetidin-3-ol 344

3-[(1S)-1-aminopropyl]-1-({3-[(2- fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)azetidin-3-ol 345

1-({3-[(2-fluoro-4- iodophenyl)amino]pyridin-4- yl}carbonyl)-3-[(1S)-1-(methylamino)propyl]azetidin-3-ol 346

(1R,2S)-4-({(1S)-1-[1-({2-fluoro-3- [(2-fluoro-4-iodophenyl)amino]pyridin-4- yl}carbonyl)-3-hydroxyazetidin-3-yl]propyl}amino)cyclopentane-1,2- diol 347

1-({7-[(4-bromo-2- chlorophenyl)amino]-8-fluoro-4-methylcinnolin-6-yl}carbonyl)-3- [(2S)-piperidin-2-yl]azetidin-3-ol 348

1-({7-[(4-bromo-2- fluorophenyl)amino]-8-fluoro-4-methylcinnolin-6-yl}carbonyl)-3- [(2S)-piperidin-2-yl]azetidin-3-ol 349

3-[(1S)-1-aminoethyl]-1-({7-[(4- bromo-2 fluorophenyl)amino]cinnolin-6-yl}carbonyl)azetidin-3-ol 350

1-({7-[(4-bromo-2- fluorophenyl)amino]cinnolin-6-yl}carbonyl)-3-{(1S)-1-[(2-hydroxy- 2- methylcyclopentyl)amino]ethyl}azetidin-3-ol 351

1-({7-[(4-bromo-2- fluorophenyl)amino]cinnolin-6-yl}carbonyl)-3-[(1S)-1- (dimethylamino)ethyl]azetidin-3-ol 352

3-[(1S)-1-aminoethyl]-1-({5-[(2- fluoro-4-iodophenyl)amino]-1H-1,2,3-benzotriazol-6- yl}carbonyl)azetidin-3-ol 353

3-[(1S)-(dimethylamino)ethyl]-1- ({5-[(2-fluoro-4-iodophenyl)amino]-1-methyl-1H-1,2,3-benzotriazol-6- yl}carbonyl)azetidin-3-ol 354

1-({5-[(2-fluoro-4- iodophenyl)amino]-1H-1,2,3-benzotriazol-6-yl}carbonyl)-3-[(2S)- piperidin-2-yl]azetidin-3-ol 355

1-({5-[(2-fluoro-4- iodophenyl)amino]-1-methyl-1H-1,2,3-benzotriazol-6-yl}carbonyl)-3- [(2S)-piperidin-2-yl]azetidin-3-ol356

1-({5-[(2-fluoro-4- iodophenyl)amino]-1H-1,2,3-benzotriazol-6-yl}carbonyl)-3-{(1S)- 1-[(2-hydroxy-2-methylcyclopentyl)amino]ethyl} azetidin-3-ol 357

3-[(1S)-1-aminoethyl]-1-({4-fluoro- 5-[(2-fluoro-4-iodophenyl)amino]-1H-1,2,3-benzotriazol-6- yl}carbonyl)azetidin-3-ol 358

1-({4-fluoro-5-[(2-fluoro-4- iodophenyl)amino]-1H-1,2,3-benzotriazol-6-yl}carbonyl)-3-[(2S)- piperidin-2-yl]azetidin-3-ol 359

5-({3-[(1S)-1-aminoethyl]-3- hydroxyazetidin-1-yl}carbonyl)-6-[(2-fluoro-4- iodophenyl)amino]pyrimidin-2(1H)- one 360

6-[(2-fluoro-4-iodophenyl)amino]-5- ({3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}carbonyl)pyrimidin- 2(1H)-one 361

4-[(2-fluoro-4-iodophenyl)amino]-5- ({3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}carbonyl)pyrimidin- 2(1H)-one 362

5-({3-[(1S)-1-aminomethyl]-3- hydroxyazetidin-1-yl}carbonyl)-4-[(2-fluoro-4- iodophenyl)amino]pyrimidin-2(1H)- one

General Administration

In one aspect, the invention provides pharmaceutical compositionscomprising an inhibitor of MEK according to the invention and apharmaceutically acceptable carrier, excipient, or diluent. In certainother embodiments, administration may preferably be by the oral route.Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally(intravenous, intramuscular, or subcutaneous), topically, transdermally,intravaginally, intravesically, intracistemally, or rectally, in theform of solid, semi-solid, lyophilized powder, or liquid dosage forms,such as for example, tablets, suppositories, pills, soft elastic andhard gelatin capsules, powders, solutions, suspensions, or aerosols, orthe like, preferably in unit dosage forms suitable for simpleadministration of precise dosages.

The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent, and,in addition, may include carriers and adjuvants, etc.

Adjuvants include preserving, wetting, suspending, sweetening,flavoring, perfuming, emulsifying, and dispensing agents. Prevention ofthe action of microorganisms can be ensured by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, and the like. It may also be desirable to include isotonic agents,for example sugars, sodium chloride, and the like. Prolonged absorptionof the injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

If desired, a pharmaceutical composition of the invention may alsocontain minor amounts of auxiliary substances such as wetting oremulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylated hydroxytoluene, etc.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area i.e., decreasing particle size.For example, U.S. Pat. No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a crosslinked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

One specific route of administration is oral, using a convenient dailydosage regimen that can be adjusted according to the degree of severityof the disease-state to be treated.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid, (b) binders, as for example, cellulosederivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose,and gum acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, croscarmellose sodium, complexsilicates, and sodium carbonate, (e) solution retarders, as for exampleparaffin, (f) absorption accelerators, as for example, quaternaryammonium compounds, (g) wetting agents, as for example, cetyl alcohol,and glycerol monostearate, magnesium stearate and the like (h)adsorbents, as for example, kaolin and bentonite, and (i) lubricants, asfor example, talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In thecase of capsules, tablets, and pills, the dosage forms may also comprisebuffering agents.

Solid dosage forms as described above can be prepared with coatings andshells, such as enteric coatings and others well known in the art. Theymay contain pacifying agents, and can also be of such composition thatthey release the active compound or compounds in a certain part of theintestinal tract in a delayed manner. Examples of embedded compositionsthat can be used are polymeric substances and waxes. The activecompounds can also be in microencapsulated form, if appropriate, withone or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Suchdosage forms are prepared, for example, by dissolving, dispersing, etc.,a compound(s) of the invention, or a pharmaceutically acceptable saltthereof, and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike; solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycoldimethylformamide: oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan; or mixtures of these substances, and the like, to thereby forma solution or suspension.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are, for example, suppositoriesthat can be prepared by mixing the compounds of the present inventionwith for example suitable non-irritating excipients or carriers such ascocoa butter, polyethyleneglycol or a suppository wax, which are solidat ordinary temperatures but liquid at body temperature and therefore,melt while in a suitable body cavity and release the active componenttherein.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the invention, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. In one example, the composition will bebetween about 5% and about 75% by weight of a compound(s) of theinvention, or a pharmaceutically acceptable salt thereof, with the restbeing suitable pharmaceutical excipients.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state in accordance with the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptablesalts or hydrates, are administered in a therapeutically effectiveamount which will vary depending upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of the compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular disease-states, and the hostundergoing therapy. The compounds of the present invention can beadministered to a patient at dosage levels in the range of about 0.1 toabout 1,000 mg per day. For a normal human adult having a body weight ofabout 70 kilograms, a dosage in the range of about 0.01 to about 100 mgper kilogram of body weight per day is an example. The specific dosageused, however, can vary. For example, the dosage can depend on a numberof factors including the requirements of the patient, the severity ofthe condition being treated, and the pharmacological activity of thecompound being used. The determination of optimum dosages for aparticular patient is well known to one of ordinary skill in the art.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described above andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention may alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

Representative pharmaceutical formulations containing a compound ofFormula I are described below in the Pharmaceutical CompositionExamples.

UTILITY

Certain compounds of this invention have been tested using the assaydescribed in Biological Example 1 and have been determined to be MEKinhibitors. As such compounds of Formula I are useful for treatingdiseases, particularly cancer in which MEK activity contributes to thepathology and/or symptomotology of the disease. For example, cancer inwhich MEK activity contributes to its pathology and/or symptomotologyinclude malignant melanomas, colorectal cancer, pancreatic cancer, lungcancer, papillary and anaplastic thyroid cancer, and endometriod ovariancancers, and the like.

Suitable in vitro assays for measuring MEK activity and the inhibitionthereof by compounds are known in the art. For example, see WO2006/061712 for measuring MEK1 and MEK2 in vitro. For further details ofan in vitro assay for measuring MEK activity see Biological Examples,Example 1 infra. Following the examples disclosed herein, as well asthat disclosed in the art, a person of ordinary skill in the art candetermine the inhibitory activity of a compound of this invention.

J Assays for measurement of in vitro efficacy in treatment of cancer areknown in the art. For example, see WO 2006/061712, which is hereinincorporated by reference, for cell-based assays for colon cancer. Inaddition, cell-based tumor models are described in Biological Examples,Example 2 and 3 infra.

Suitable in vivo models for cancer are known to those of ordinary skillin the art (including WO 2006/061712). For further details of in vivomodels for colorectal cancer, melanoma, breast adenocarcinoma, and lunganaplastic carcinoma, see Biological Example 4, infra.

GENERAL SYNTHESIS

Compounds of this invention can be made by the synthetic proceduresdescribed below. The starting materials and reagents used in preparingthese compounds are either available from commercial suppliers such asAldrich Chemical Co. (Milwaukee, Wis.), or Bachem (Torrance, Calif.), orare prepared by methods known to those skilled in the art followingprocedures set forth in references such as Fieser and Fieser's Reagentsfor Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd'sChemistry of Carbon Compounds, Volumes 1-5 and Supplementals (ElsevierScience Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wileyand Sons, 1991), March's Advanced Organic Chemistry, (John Wiley andSons, 4^(th) Edition) and Larock's Comprehensive Organic Transformations(VCH Publishers Inc., 1989). These schemes are merely illustrative ofsome methods by which the compounds of this invention can besynthesized, and various modifications to these schemes can be made andwill be suggested to one skilled in the art having referred to thisdisclosure. The starting materials and the intermediates of the reactionmay be isolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure and over a temperature range from about−78° C. to about 150° C., more preferably from about 0° C. to about 125°C. and most preferably at about room (or ambient) temperature, e.g.,about 20° C. Unless otherwise stated (as in the case of anhydrogenation), all reactions are performed under an atmosphere ofnitrogen.

Prodrugs can be prepared by techniques known to one skilled in the art.These techniques generally modify appropriate functional groups in agiven compound. These modified functional groups regenerate originalfunctional groups by routine manipulation or in vivo. Amides and estersof the compounds of the present invention may be prepared according toconventional methods. A thorough discussion of prodrugs is provided inT. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

The compounds of the invention, or their pharmaceutically acceptablesalts, may have asymmetric carbon atoms or quaternized nitrogen atoms intheir structure. Compounds of Formula I that may be prepared through thesyntheses described herein may exist as single stereoisomers, racemates,and as mixtures of enantiomers and diastereomers. The compounds may alsoexist as geometric isomers. All such single stereoisomers, racemates andmixtures thereof, and geometric isomers are intended to be within thescope of this invention. Some of the compounds of the invention mayexist as tautomers. For example, where a ketone or aldehyde is present,the molecule may exist in the enol form; where an amide is present, themolecule may exist as the imidic acid; and where an enamine is present,the molecule may exist as an imine. All such tautomers are within thescope of the invention.

The present invention also includes N-oxide derivatives and protectedderivatives of compounds of Formula I. For example, when compounds ofFormula I contain an oxidizable nitrogen atom, the nitrogen atom can beconverted to an N-oxide by methods well known in the art. When compoundsof Formula I contain groups such as hydroxy, carboxy, thiol or any groupcontaining a nitrogen atom(s), these groups can be protected with asuitable “protecting group” or “protective group”. A comprehensive listof suitable protective groups can be found in T.W. Greene, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, Inc. 1991, thedisclosure of which is incorporated herein by reference in its entirety.The protected derivatives of compounds of Formula I can be prepared bymethods well known in the art.

Methods for the preparation and/or separation and isolation of singlestereoisomers from racemic mixtures or non-racemic mixtures ofstereoisomers are well known in the art. For example, optically active(R)- and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. Enantiomers (R- andS-isomers) may be resolved by methods known to one of ordinary skill inthe art, for example by: formation of diastereoisomeric salts orcomplexes which may be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which may be separated, forexample, by crystallization, selective reaction of one enantiomer withan enantiomer-specific reagent, for example enzymatic oxidation orreduction, followed by separation of the modified and unmodifiedenantiomers; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support, such as silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where a desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step may be required to liberate the desired enantiomeric form.Alternatively, specific enantiomer may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents or by converting on enantiomer to the other by asymmetrictransformation. For a mixture of enantiomers, enriched in a particularenantiomer, the major component enantiomer may be further enriched (withconcomitant loss in yield) by recrystallization.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

The chemistry for the preparation of the compounds of this invention isknown to those skilled in the art.

An intermediate of Formula II:

where R⁷, X, R¹⁰, R¹², R¹⁴, and R¹⁶ are as defined in the Summary of theInvention for Group A can be prepared using procedures known to one ofordinary skill in the art. In particular, see (for example) U.S. Pat.No. 7,019,033, WO 2002006213, WO 2003062191, WO 2003062189, WO2002018319, WO2001005392, WO 2000064856, WO 2001005392, WO 9901421, WO2004056789, Davis, E. M. et al. Org. Process Res. & Dev. 2005, 9, 843-6,and Shapiro, N. et al. Synthetic Commun. 2005, 35, 2265-9 which areincorporated by reference herein. The following intermediates wereprepared using similar procedures as described in the above references:3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid;2-[(2-chloro-4-iodophenyl)amino]-3,4-difluorobenzoic acid;4-fluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid;4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid; and2-[(4-bromo-2-fluorophenyl)amino]-3,4-difluorobenzoic acid.

An intermediate of Formula III(a) or III(b):

where R⁷, X, R¹⁰, R², and R¹⁴ are as defined in the Summary of theInvention for Group H can be prepared using procedures known to one ofordinary skill in the art. In particular for formula III(a), where R¹⁴is amino or alkyl (particularly methyl); R¹⁰ is halo (particularlyfluoro); R⁷ is hydrogen or halo (particularly bromo or chloro); X ishalo (particularly chloro); and R¹² is hydrogen see for exampleWO2006030610, US2005049419, and US2005/0054701 which are incorporated byreference herein.6-[(4-bromo-2-chlorophenyl)amino]-7-fluoro-3-methyl-1,2-benzisoxazole-5-carboxylicacid was prepared using methods similar to those disclosed inWO2006030610, US2005049419, and US2005/0054701.

An intermediate of Formula IV(a) or IV(b):

where R⁷, X, R¹⁰, R¹¹, and R¹⁴ are as defined in the Summary of theInvention for Group B can be prepared using procedures known to one ofordinary skill in the art.

An intermediate of Formula V(a) or V(b):

where R⁷, X, R¹⁰, R¹², R¹⁴, and R¹⁹ are as defined in the Summary of theInvention for Group B can be prepared using procedures known to one ofordinary skill in the art. In particular the halo precursor of V(a) canbe prepared using, for example, WO2003101968 and WO2002083648 which areincorporated by reference herein. In particular the halo precursor ofV(b) can be prepared using, for example, US2004192653, US2004180896,US2004176325 which are incorporated by reference herein. The haloprecursors are then reacted with an appropriate aniline to yield theintermediates of Formula V(a) and V(b).

An intermediate of Formula VI(a) or VI(b):

where R⁷, X, R¹⁰, R¹², and R¹⁴ are as defined in the Summary of theInvention for Group B can be prepared using procedures known to one ofordinary skill in the art. In particular, for VI(b) see for exampleWO2000042022 and WO2001005390 which are incorporated by referenceherein.

An intermediate of Formula VII(a) or VII(b):

where R⁷, X, R¹⁰, R¹², and R¹⁴ are as defined m the Summary of theInvention for Group B can be prepared using procedures known to one ofordinary skill in the art. For intermediate VII(b) see, for example,WO2001005390 and WO2000042022 which are incorporated by referenceherein.

An intermediate of Formula VIII(a) or VIII(b):

where R⁷, X, R¹⁰, R¹², R¹⁴, and R¹⁴ are as defined in the Summary of theInvention for Group B can be prepared using procedures known to one ofordinary skill in the art. In particular for formula VIII(b) where R¹⁰is halo (particularly fluoro), R¹² is hydrogen, R¹⁴ is hydrogen, and R¹⁹is hydrogen or alkyl (particularly methyl) or alkenyl (particularlyallyl), see WO 05/023251, WO2005009975, and WO2001005390 which areincorporated by reference herein. In particular for VIII(a) where X ishalo (particularly chloro or fluoro) or alkyl (particularly methyl), R⁷is halo (particularly iodo, bromo, or chloro) or haloalkoxy(particularly trifluoromethoxy), R¹⁰ is halo (particularly fluoro orchloro), R¹⁴ is hydrogen or alkyl (particularly methyl), and R¹⁹ ishydrogen or alkyl (particularly methyl), see for example US2004/0116710, WO 03/077914, WO 03/077855, WO 00/42022, WO2005009975, andWO2001005390 which are incorporated by reference herein. The followingintermediates were prepared using similar procedures described in US2004/0116710, WO 03/077914, WO 03/077855, WO 00/42022, WO2005009975, andWO2001005390:5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-1-methyl-1H-benzimidazole-6-carboxylicacid and4-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-1-methyl-1H-benzimidazole-6-carboxylicacid.

An intermediate of Formula IX:

where R⁷, X, R¹⁰, R¹², R¹⁴, and R¹⁶ are as defined in the Summary of theInvention for Group B can be prepared using procedures known to one ofordinary skill in the art. In particular, where R¹⁰ is hydrogen or halo(particularly chloro or fluoro); R¹² is hydrogen; R¹⁴ is hydrogen,amino, alkylamino, or dialkylamino; R¹⁶ is hydrogen; X is halo(particularly chloro); and R⁷ is halo (particularly bromo) see forexample WO 05/023759, US 2005/0054701, US 2006030610, US 2005049419, andUS 2005049276 which are incorporated by reference herein. The followingintermediates were prepared using similar procedures as those describedin WO 05/023759, as well as US 2006030610 and US 2005/0054701:7-[(4-bromo-2-chlorophenyl)amino]-8-chloroimidazo[1,2-a]pyridine-6-carboxylicacid and8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[,2-a]pyridine-6-carboxylicacid. The following intermediates can be prepared using similarprocedures described in the references given above:8-Fluoro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridine-6-carboxylicacid and7-[(4-Bromo-2-fluorophenyl)amino]-8-fluoroimidazo[1,2-a]pyridine-6-carboxylicacid.

An intermediate of Formula X(a) and X(b):

where R⁷, X, R¹⁰, R¹², and R¹⁴ are as defined in the Summary of theInvention for Group B can be prepared using procedures known to one ofordinary skill in the art. In particular, where R¹⁰ is hydrogen, halo(specifically chloro), or alkyl (specifically methyl), R¹² is hydrogen,and R¹⁴ is hydrogen, halo (specifically bromo), see for example WO06/045514 which is incorporated by reference herein. To prepare theintermediate of Formula X(b), the nitrogen in the pyridine ring of X(a)can then be oxidized with an agent such as MCPBA or H₂O₂. The followingX(a) and X(b) intermediates were prepared using similar methods asdisclosed in WO 06/045514:3-[(2-Fluoro-4-iodophenyl)amino]pyridine-4-carboxylic acid and3-[(2-Fluoro-4-iodophenyl)amino]pyridine-4-carboxylic acid 1-oxide. Thefollowing X(a) intermediates can be prepared using similar methods asdisclosed in WO 06/045514:2-Fluoro-3-[(2-fluoro-4-iodophenyl)amino]pyridine-4-carboxylic acid and3-[(4-Bromo-2-fluorophenyl)amino]pyridine-4-carboxylic acid.

An intermediate of Formula XI(a):

where R⁷, X, R¹⁰, R¹², and R¹⁴ are as defined in the Summary of theInvention for Group B can be prepared using procedures known to one ofordinary skill in the art. In particular, where R¹⁰ is hydrogen, R¹² ishydrogen or halo (particularly chloro or fluoro), R¹⁴ is amino or halo(particularly chloro), X is halo (particularly chloro), and R⁷ is halo(particularly bromo) see for example US 2005/0054701, US 200549419, andUS 2006030610 which are incorporated by reference herein. Theintermediate of Formula XI(b) can be prepared by oxidizing the nitrogenin the pyridine ring of XI(a) with an agent such as MCPBA or H₂O₂.

An intermediate of Formula XII:

where R⁷, X, R¹⁰, R¹², R¹⁴, and R¹⁶ are as defined in the Summary of theInvention for Group B can be prepared using procedures known to one ofordinary skill in the art. In particular, see for example WO 05/051302which is incorporated by reference herein. The following intermediatescan be prepared using similar methods as disclosed in WO 05/051302:8-Fluoro-7-[(2-fluoro-4-iodophenyl)amino]-4-methylcinnoline-6-carboxylicacid;7-[(4-Bromo-2-chlorophenyl)amino]-8-fluoro-4-methylcinnoline-6-carboxylicacid;7-[(4-Bromo-2-fluorophenyl)amino]-8-fluoro-4-methylcinnoline-6-carboxylicacid; and 7-[(4-Bromo-2-fluorophenyl)amino]cinnoline-6-carboxylic acid.

An intermediate of Formula XIII:

where R⁷, X, R¹⁰, R^(10a), and Y¹ are as defined in the Summary of theInvention for Group C can be prepared using procedures known to one ofordinary skill in the art, including for example the procedures in U.S.Ser. No. 05/025,6123, Wallace, E. M. et al. J. Med. Chem. 2006, 49,441-4, WO 2005000818, and WO 2005051301 (where Y¹ is carbon) which areincorporated by reference herein.4-[(4-Bromo-2-fluorophenyl)amino]-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid was prepared using similar procedures to those disclosed in U.S.Ser. No. 05/025,6123 and WO 2005051301.4-Chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid wasprepared using similar procedures to those disclosed in US 2005256123.The following intermediates can be prepared using the methods disclosedin the above references:

-   4-[(2-Fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic    acid;-   4-[(4-Bromo-2-chlorophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic    acid;-   4-[(4-Bromo-2-fluorophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic    acid;-   4-[(4-Bromo-2-chlorophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic    acid;-   4-[(4-Bromo-2-chlorophenyl)amino]-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic    acid; and-   4-[(4-Bromo-2-fluorophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic    acid.

An intermediate of Formula XIV:

where R⁷, X, R¹⁰, and R¹⁴ are as defined in the Summary of the Inventionfor Group B can be prepared using procedures known to one of ordinaryskill in the art. In particular, see for example WO 05/051302 which isincorporated by reference herein.

An intermediate of Formula IVI

where X and R⁷ are as defined in the Summary of the Invention for aCompound of Group B can be prepared using procedures known to one ofordinary skill in the art. In particular, see for example WO 2001005390and WO 2000042022 for procedures that can be used to prepare thefollowing:5-[(2-Fluoro-4-iodophenyl)amino]-1H-benzotriazole-6-carboxylic acid;5-[(2-Fluoro-4-iodophenyl)amino]-1-methyl-1H-benzotriazole-6-carboxylicacid; and4-Fluoro-5-[(2-fluoro-4-iodophenyl)amino]-1H-benzotriazole-6-carboxylicacid.

An intermediate of Formula XVII

where X and R⁷ are as defined in the Summary of the Invention for aCompound of Group B can be prepared using procedures known to one ofordinary skill in the art. In particular, see Example 29.

An intermediate of Formula XVIII(a) or XVIII(b)

where X, R⁷, R⁴⁰, and R^(40a) are as defined in the Summary of theInvention for a Compound of Group D can be prepared using proceduresknown to one of ordinary skill in the art. In particular, the haloprecursors to XVIII(a) and XVIII(b)

respectively can be prepared using procedures similar to those describedin Machon and Dlugosz Acta Poloniae Pharmaceutica 1983, 40(1), 1-6 andvon Angerer, Science of Synthesis 2004, 16, 379-572 (General Reviewwritten in English). The halo precursors are then reacted with

using procedures known to one of ordinary skill in the art and thesynthetic methods disclosed herein. The following intermediates can beprepared as described above:6-[(2-fluoro-4-iodophenyl)amino]-2-oxo-1,2-dihydropyrimidine-5-carboxylicacid and4-[(2-fluoro-4-iodophenyl)amino]-2-oxo-1,2-dihydropyrimidine-5-carboxylicacid.

An intermediate of Formula XIX

where X and R⁷ are as defined in the Summary of the Invention for aCompound of Group C can be prepared using methods known to one ofordinary skill in the art. In particular see US 2005049276.

An intermediate of Formula XX

where X and R⁷ are as defined in the Summary of the Invention for aCompound of Group C can be prepared using methods known to one ofordinary skill in the art. In particular see US 2005049276.

The synthesis of azetidines substituted at the 3-position can beconveniently carried out according to Scheme 1:

starting from the N-diphenylmethyl protected azetidin-3-ol (1), readilyprepared by reaction of epichlorohydrin and diphenylmethylamine(Chatterjee, Shym S.; Triggle, D. J. Chemical Communications (London)1968, 2, 93). Protecting group exchange, from Boc to CBz, on theazetidine is carried out according to literature protocols (Greene, T.W., Wuts, P. O. Protective Groups in Organic Synthesis,Wiley-Interscience) and subsequent oxidation to the azetidinone (2)where P is CBz provides a useful intermediate for the preparation ofcompounds of the invention.

For example, the ketone intermediates of formula 2 can be broadlyfunctionalized at the 3-position according to Scheme 2.

An intermediate of formula (3), where R⁴ is as defined in the Summary ofthe Invention for a compound of Group A, Group B, Group C, or Group Dcan be prepared by reacting the intermediate 2 with Grignard reagents orother organometallic species of formula 17, such as organolithiums.Alternatively, the intermediate 2 can be reacted with nitroalkane anionsof formula 18 prepared in-situ as in the henry reaction (The Henryreaction, recent examples: Luzzio, F. A. Tetrahedron 2001, 57(6),915-945) to give (4) where R⁴′ is hydrogen or alkyl optionallysubstituted as described for R⁴ in the Summary of the Invention for acompound of Group A, Group B, Group C, or Group D. Alternatively, theintermediate 2 can be reacted with ketone or aldehyde anions of formula19 in a Claisen-type condensation to give (5) where R^(4′) is alkyloptionally substituted as described for R⁴ in the Summary of theInvention for a compound of Group A, Group B, Group C, or Group D and R⁴is hydrogen or R⁴′. In addition, 2 can be reacted with Wittig reagentsof formula 20 (where R′ and R″ are independently hydrogen, alkyl,alkenyl, aryl, or heteroaryl and the alkyl, alkenyl, aryl, andheteroaryl are optionally substituted as described for R⁴ in the Summaryof the Invention for a compound of Group A, Group B, Group C, or GroupD) to prepare intermediates of formula 6, which are also useful asprecursors for compounds of the invention.

According to Scheme 3, intermediates of formula (6) where where (R′ andR″ are hydrogen and P is a nitrogen-protecting group such as CBz or Boc)

can be further converted to the corresponding epoxide (7) and subsequentreaction with a suitable nitrogen base or other nucleophiles may becarried out to give access to a broad range of azetidin-3-ol derivativessuch as (8), where R⁸ and R^(8′) are as defined in the Summary of theInvention.

In some cases the preparation of optically pure compounds is desiredwhere the azetidine contains one or more stereocenters. Numeroustechniques for the preparation of optically pure compounds through bothresolution techniques and asymmetric synthesis are well known in theart. In one such case, an asymmetric synthesis methodology can beemployed where an azetidine precursor of formula (2) is reacted with anintermediate of formula 21 where R′ is not hydrogen, as depicted inScheme 4.

One such useful approach makes use of Evans oxazolidinone methodology(Diastereoselective aldol condensation using a chiral oxazolidinoneauxiliary. Gage, James R.; Evans, David A. Organic Syntheses 1990, 68,83-91). The condensation of an azetidinone (2) with the a chiraloxazolidinone in the presence of a base such as LDA affords anintermediate oxazolidinone (9), where P is a nitrogen-protecting groupsuch as CBz or Boc, with diastereoselectivity. Treatment with lithiumhydroxide in aqueous hydrogen peroxide gives carboxylic acid (10) whichcan be subject to Curtius rearrangement to provide the chiraloxazolidinone (11) then carried forward as required to a usefulintermediate (12). Further protecting group manipulation andderivatization as required can be employed to prepare compounds ofFormula I.

Alternatively, a racemic mixture of an intermediate of formula (13),useful to prepare a compound of Formula I where R³ is hydroxy and R⁴ isheterocycloalkyl (in particular, where R⁴ is a N-protected piperidine),can be prepared according to Scheme 5.

In the reaction schemes P¹ and P² are orthogonal nitrogen-protectinggroups. For example, P¹ is Boc and P² is CBz or P¹ is CBz and P² is Boc.The reaction is carried out in-situ by treating 22 to generate thelithated amine and by subsequently treating it with a ketone such as (2)according to the method of Peter Beak (Beak, Peter, Lee, Won Kooα-Lithioamine synthetic equivalents: syntheses of diastereoisomers fromthe Boc-piperidines. Journal of Organic Chemistry 1990, 55(9), 2578-80).The racemate (13) thus prepared can be resolved by functionalization, asdepicted in Scheme 6, with a chiral acid such as the readily-availableMosher acid (14).

The resulting diastereomeric esters (15) can be separated bychromatographic means and then carried forward individually as theenantiomerically pure intermediates (R)-(16) and (S)-(16).

Compounds of the Invention can be prepared by reacting an intermediateof Formula II, III(a), III(b), IV(a), IV(b), V(a), V(b), VI(a), VI(b),VII(a), VII(b), VIII(a), VIII(b), IX, X(a), X(b), XI(a), XI(b), XII,XIII, XIV, XVI, XVII, XVIII(a), XVIII(b), XIX, or XX with intermediate17 according to Scheme 7:

The reaction is carried out in a solvent such as DMF, THF, or DCM in thepresence of a base such as DIPEA, N-methylmorpholine, DMAP, ortriethylamine and optionally in the presence of a coupling agent such asPyBOP, HBTU, or EDCI.

Alternatively an intermediate of Formula II, III(a), III(b), IV(a),IV(b), V(a), V(b), VI(a), VI(b), VII(a), VII(b), VIII(a), VIII(b), IX,X(a), X(b), XI(a), XI(b), XII, XIII, XIV, XVI, XVII, XVII(a), XVIII(b),XIX, or XX can be converted into an acid halide according

where X² is halo, such as chloro or fluoro, and all other groups are asdefined in the Summary of the Invention for a compound of Group A, GroupB, Group C, or Group D. The reaction is carried out in a solvent such asdioxane, THF, or DCM in the presence of a base such as DIPEA, sodiumbicarbonate. The acid halide of formula 18 can then be reacted with anazetidine intermediate of formula 17 to prepare a compound of Formula I.

SYNTHETIC EXAMPLES

Generally, the compounds listed below were identified by IC-MS, and/orisolated, and characterized by ¹H-NMR (most typically 400 MHz). Liquidchromatography-mass spectral (LC-MS) analyses were performed using atleast one of: a Hewlett-Packard Series 1100 MSD, an Agilent 1100 SeriesLC/MSD (available from Agilent Technologies Deutschland GmbH ofWaldbronn Germany), or a Waters 8-Channel MUX System (available fromWaters Corporation of Milford, Mass.). Compounds were identifiedaccording to either their observed mass [MH⁺] or [MNa⁺] ion (positivemode) or [MH⁻] ion (negative mode). ¹H-NMR data for compounds was takenwith a Varian AS400 Spectrometer (400 MHz, available from Varian GmbH,Darmstadt, Germany). Starting materials and intermediates used toprepare a compound of the invention are either commercially available orcan be prepared by one of ordinary skill in the art.

Reference 1 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino] benzoylfluoride

To a stirred mixture of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (12 g, 30.5 mmol), prepared using procedures similar tothose described in U.S. Pat. No. 7,019,033, in dichloromethane (70 mL)at 0° C. was added pyridine (2.5 mL, 30.8 mmol) followed by dropwiseaddition of cyanuric fluoride (2.8 mL, 33.6 mmol). The reaction mixturewas stirred at 0° C. for 10 minutes and then warmed to room temperatureand stirred for 2 hours. The reaction mixture was diluted with water andextracted with dichloromethane (100 mL). The aqueous layer was extractedonce with dichloromethane (50 mL). The combined organic layers werewashed with saturated aqueous sodium bicarbonate solution, brine, driedover anhydrous sodium sulfate and concentrated in vacuo to give crudeproduct as a brownish solid. Crude product was purified by flashchromatography (plug, 25% ethyl acetate in hexanes) to afford3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino] benzoyl fluoride as abeige solid (11.8 g, 97% yield). ¹H NMR (400 MHz, CD₃OD): 8.41 (s, 1H),7.80-7.81 (m, 1H), 7.52 (dd, 1H), 7.43-7.47 (m, 1H), 6.96-7.03 (m, 1H),6.85-6.92 (m, 1H).

Reference 2 2-[(4-bromo-2-chlorophenyl)amino]-3,4-difluorobenzoic Acid

To a solution of 2,3,4-trifluorobenzoic acid (1 g, 5.68 mmol) and4-bromo-2-chloroaniline (1.2 g. 5.68 mmol) in acetonitrile (10 mL) wasadded lithium amide (0.39 g, 17.04 mmol) and the reaction stirred at 60°C. for 1.5 hours. The mixture was cooled to room temperature and then to0° C. and acidified with aq. hydrochloric acid. The obtained precipitatewas collected by filtration and washed with cold water and dried invacuo to afford 2-[(4-bromo-2-chlorophenyl)amino]-3,4-difluorobenzoicacid (1.92 g, 94% yield) as a beige solid. MS (EI) for C₁₃H₇BrClF₂NO₂:363 (MH⁺).

Using the same or analogous synthetic techniques and substituting, asnecessary, with alternative reagents,2-[(4-iodo-2-fluorophenyl)amino]-3-fluorobenzoic acid was prepared. MS(EI) for C₁₃H₈F₂INO₂: 376 (MH⁺).

Reference 3 Phenylmethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate

To a solution of azetidin-3-ol hydrochloride in tetrahydrofuran (90 mL)and water (10 mL) was added triethylamine (15 mL, 0.106 mol) followed byslow addition of benzyl chloroformate (8.0 mL, 0.056 mol) at roomtemperature. The reaction mixture was stirred at room temperature for 16hours then partitioned with water and ethyl acetate. The organic layerwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by flash chromatography (SiO₂,25-50% ethyl acetate in hexanes) to afford phenylmethyl3-hydroxyazetidine-1-carboxylate (3.56 g, 33% yield) as a clear andcolorless oil. ¹H NMR (400 MHz, CDCl₃): 7.36-7.31 (m, 5H), 5.09 (s, 2H),4.64-4.57 (m, 1H), 4.22 (dd, 2H), 3.88 (dd, 2H), 2.61 (d, 1H, J=4.0 Hz).MS (EI) for C₁₁H₁₃NO₃: 208 (MH⁺).

To a solution of phenylmethyl 3-hydroxyazetidine-1-carboxylate (3.5 g,0.0168 mol) in dichloromethane (100 mL) was added Dess-Martinperiodinane (10.7 g, 0.0.25 mol) at room temperature and stirred for 5h. The reaction mixture was quenched with 1:1 ratio of saturated aqueoussodium bicarbonate and IM sodium thiosulfate (200 mL) and thenpartitioned with dichloromethane. The organic layer was dried overanhydrous magnesium sulfate and concentrated in vacuo to affordphenylmethyl 3-oxoazetidin-1-carboxylate (3.43 g, 99% yield) as a clearand colorless oil without further purification. ¹H NMR (400 MHz, CDCl₃):7.39-7.31 (m, 5H), 5.17 (s, 2H), 4.77 (s, 4H). MS (EI) for CH₁₁H₁₁NO₃:205 (M⁺).

A suspension of methyltriphenylphosphonium bromide (23.0 g, 0.0649 mol)and potassium tert-butoxide (7.3 g, 0.0649 mol) in diethyl ether (140mL) was stirred at room temperature for 20 min, and then heated to 35°C. for 1 h. To this bright yellow reaction mixture was slowly added adilute solution of phenylmethyl 3-oxoazetidine-1-carboxylate (3.33 g,0.0162 mol) in diethyl ether (50 mL). The reaction mixture was stirredat 35° C. for 12 hours then filtered through a bed of celite and rinsedwith ethyl ether. The filtrate was washed with water and brine, driedover anhydrous magnesium sulfate and concentrated. The residue waspurified by flash chromatography (SiO₂, 5-10% ethyl acetate in hexanes)to afford phenylmethyl 3-methylideneazetidine-1-carboxylate (2.46 g, 75%yield) as a clear and colorless oil). ¹H NMR (400 MHz, CDCl₃): 7.27-7.22(m, 5H), 5.02 (s, 2H), 4.93-4.90 (m, 2H), 4.48-4.47 (m, 4H). MS (EI) forC₁₂H₁₃NO₂: 203 (M⁺).

To a solution of phenylmethyl 3-methylideneazetidine-1-carboxylate (2.46g, 0.0121 mol) in chloroform (100 mL) was added 3-chloroperoxybenzoicacid (12.5 g, 0.0726 mol) at 0° C. The reaction mixture was allowed towarm up to room temperature over a period of 12 hours then quenched with1 M sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1). Thelayers were separated and the organic layer was dried over anhydrousmagnesium sulfate then concentrated. The residue was purified by flashchromatography (5-15% ethyl acetate in hexanes) to afford phenylmethyl1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (2.2 g, 83% yield) as clearand colorless oil. ¹H NMR (400 MHz, CDCl₃): 7.37-7.29 (m, 5H), 5.12 (s,2H), 4.35-4.26 (m, 4H), 2.85 (s, 2H). MS (EI) for C₁₂H₁₃NO₃: 220 (MH⁺).

Reference 44-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylicAcid

4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid wasprepared using procedures similar to those disclosed in US 2005256123.

To a solution of4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (350 mg,1.855 mmol) and 2-fluoro-4-iodoaniline (1.06 g, 4.453 mmol) intetrahydrofuran (13.3 mL) was sparged with nitrogen for 5 minutesfollowed by the slow addition of lithium bis(trimethylsilyl)amide, 1.0 Min THF (7.4 mL). The reaction mixture stirred for an additional 4 hoursat room temperature. The mixture was quenched with 1 N HCl andconcentrated in vacuo. The residue was partitioned between ethyl acetateand 1 N aqueous HCl. The aqueous layer was extracted (3×) with ethylacetate. The combined organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and evaporated to afford4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylicacid (939 mg, 100% yield). ¹H NMR (CDCl₃): 7.27 (dd, 1H), 7.21 (d, 1H),6.54 (t, 1H), 4.84 (broad s, 2H), 2.09 (s, 1H), 1.26 (t, 3H); MS (EI)for C₁₂H₉N₃O₃FI: 389 (MH⁺).

A solution of4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylicacid (939 mg, 2.413 mmol) in dichloromethane (60 mL) in the presence ofdimethylformamide (8.0 mL) was cooled to 0° C. Malonyl chloride (1.26mL, 14.48 mmol) was added and stirred at room temperature for 1 hour.The reaction mixture was evaporated and partitioned between ethylacetate and IM aqueous ammonium chloride. The aqueous layer wasextracted 1× with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to afford4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonylchloride. This crude material was taken into the next step withoutfurther purification. MS (EI) for C₁₂H₈N₃O₂ClFI: 408 (MH⁺).

To a solution of4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonylchloride in methanol (15 mL) and benzene (12 mL) was added dropwisetrimethylsilyl diazomethane (1 mL) and stirred at room temperature for15 minutes. The reaction mixture was quenched with acetic acid andevaporated. The residue was partitioned between ethyl acetate and brine.The organic layer was separated, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was purified on silicagel chromatography column (7:3 hexanes/ethyl acetate) to afford methyl4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate(84.9 mg, 8.7% yield). H NMR (CDCl₃): 7.49-7.56 (m, 3H), 7.12 (t, 1H),6.13 (d, 1H), 4.00 (s, 3H), 3.83 (s, 3H); MS (EI) for C₁₃H₁₁N₃O₃F: 404(MH⁺).

Methyl4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate(84.9 mg, 0.211 mmol) was dissolved in tetrahydrofuran (5 mL), methanol(2.5 mL) and water (2.5 mL). Aqueous 2 M lithium hydroxide (200 μL) wasadded at room temperature. After 10 minutes, the reaction mixture washeated to 50° C. for 30 minutes and continued to stir at roomtemperature for 16 hours at which time the solvents were evaporated. Theresidue was made acidic with 2 M aqueous hydrochloric acid to pH 2 andextracted with ethyl acetate. The organic layer separated, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to provide4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylicacid (54.0 mg, 66% yield). MS (EI) for C₁₂H₉N₃O₃FI: 390 (MH⁺).

Reference 5 1,1-dimethylethyl2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate

To a solution of 1,1-dimethylethyl piperidine-1-carboxylate (0.50 g, 2.7mmol) in anhydrous diethyl ether (9.0 mL) under anhydrous nitrogen gaswas added N,N,N′,N′-tetramethylethane-1,2-diamine (0.41 mL, 2.7 mmol),and the solution was cooled to −78° C. To this solution was added(2-methylpropyl)lithium (2.1 mL, 1.4 M in cyclohexane, 3.0 mmol) insmall portions. To this anion solution was added phenylmethyl3-oxoazetidine-1-carboxylate (1.0 g, 5.4 mmol), prepared usingprocedures as described in Reference 3, in anhydrous ether (2.0 mL),while maintaining the internal temperature at less than −60° C. Thesolution was allowed to warm to room temperature and stirred overnight.The reaction was quenched with water, and partitioned between water anddiethyl ether. The layers were separated and the aqueous layer wasextracted with diethyl ether twice. The combined organic layers weredried (magnesium sulfate), filtered and concentrated in vacuo.Chromatography (silica gel, 3:1 hexanes/ethyl acetate) gave 0.13 g (13%)of 1,1-dimethylethyl2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate.¹H NMR (400 MHz, CDCl₃): 7.31 (m, 5H), 5.08 (s, 2H), 4.05 (d, 1H), 4.00(d, 1H), 3.84 (d, 2H), 3.80 (broad s, 1H), 3.55 (broad s, 1H), 3.10(broad s, 1H), 1.92 (m, 1H), 1.45-1.62 (m, 6H), 1.43 (s, 9H). MS (EI)for C₂₁H₃₀N₂O₅: 335 (M-tBu), 315 (M-OtBu).

Example 11-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol

3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (2.1 g, 5.3mmol), prepared using procedures similar to those in U.S. Pat. No.7,019,033, was taken into DMF (10 mL) followed by addition of PyBOP (2.6g, 5.3 mmol) and the mixture was allowed to stir at room temperatureover 15 minutes. Azetidin-3-ol hydrochloride (870 mg, 8.0 mmol) andDIPEA (1.85 mL, 11.2 mmol) was then added and the mixture was allowed tostir an additional hour at room temperature. The mixture was thenpartitioned with ethyl acetate and 0.5 M aqueous sodium hydroxidesolution. The organic layer was then washed with water (3×) then brineand dried over anhydrous sodium sulfate. Filtration and concentrationfollowed by silica gel flash chromatography using ethyl acetate: hexanes(5:1) eluent afforded1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol(2.09 g, 87% yield) as a colorless amorphous solid. ¹H NMR (400 MHz,CDCl₃): 8.47 (s, 1H), 7.39 (dd, 1H), 7.32 (d, 1H), 7.13-7.09 (m, 1H),6.84-6.78 (m, 1H), 6.63-6.57 (m, 1H), 4.74-4.67 (m, 1H), 4.43-4.39 (m,2H), 4.20-3.96 (br d, 2H), 2.50 (d, 1H).

Using the same or analogous synthetic techniques and substituting, asnecessary, with alternative reagents, the compounds in Examples 1(a)-(c)were prepared.

Example 1(a)

1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}-carbonyl)azetidin-3-yl]-N,N-dimethylpyrrolidin-3-amine.The title compound was prepared by reacting3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid withN-methyl-N-(2-(pyridin-2-yl)ethyl)azetidin-3-amine. The azetidineintermediate was prepared using procedures similar to those described inAbdel-Magid, et. al., Tetrahedron Letters 1990, 31(39), 5595 startingwith tert-butyl 3-oxoazetidine-1-carboxylate, which itself was preparedas described in Example 3. The title compound: ¹H NMR (400 MHz,d₆-DMSO): 8.56 (s, 1H), 7.58 (m, 1H), 7.38 (d, 1H), 7.31 (m, 1H), 7.16(m, 18), 6.67 (m, 1H), 4.16 (m, 1H), 3.97 (m, 2H), 3.77 (m, 1H), 3.26(br s, 4H), 2.63 (m, 1H), 2.42 (br s, 6H), 1.99 (br s, 1H), 1.74 (br s,1H). MS (EI) for C₂₂H₂₄F₃IN₄O: 545 (MH⁺).

Example 1(b)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-methyl-N-(2-pyridin-2-ylethyl)azetidin-3-amine.The title compound was prepared by reacting3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid with1-(azetidin-3-yl)-N,N-dimethylpyrrolidin-3-amine. The azetidineintermediate was preparedusing procedures similar to those described inAbdel-Magid, et. al., Tetrahedron Letters 1990, 31(39), 5595 startingwith tert-butyl 3-oxoazetidine-1-carboxylate, which itself was preparedas described in Example 3. The title compound: ¹H NMR (400 MHz, CD₃OD):8.50 (d, 1H), 7.94 (t, 1H), 7.50-7.30 (m, 5H), 7.07 (q, 1H), 6.66-6.61(m, 1H), 4.52-4.48 (m, 2H), 4.31 (s, 2H), 4.23-4.18 (m, 1H), 3.48-3.46(m, 2H), 3.17-3.13 (m, 2H), 2.88 (s, 3H); MS(EI) for C₂₄H₂₂F₃IN₄O: 567(MH⁺).

Example 1(c)

6-(Azetidin-1-ylcarbonyl)-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline:¹H NMR (400 MHz, CDCl₃): 8.57 (s, 1H), 7.41-7.38 (dd, 1H), 7.34-7.31(dt, 1H), 7.13-7.09 (m, 1H), 6.83-6.77 (m, 1H), 6.64-6.58 (m, 1H), 4.27(b, 2H), 4.18 (b, 2H), 2.38-2.30 (p, 2H); MS (EI) for C₁₆H₁₂F₃IN₃O: 433(MH⁺).

Example 1(d)

[1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]methanol:¹H NMR (400 MHz, CDCl₃): 8.52 (s, 1H), 7.41-7.38 (dd, 1H), 7.34-7.31(dt, 1H), 7.15-7.11 (m, 1H), 6.83-6.77 (m, 18), 6.64-6.58 (m, 1H),4.29-4.20 (m, 2H), 4.09 (b, 1H), 3.93 (b, 1H), 3.82-3.81 (d, 2H),2.89-2.75 (m, 1H); MS (EI) for C₁₇H₁₄F₃IN₂O₂: 463 (MH⁺).

Example 1(c)

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxylicacid: ¹H NMR (400 MHz, CDCl₃): 7.79 (b, 2H), 7.42-7.38 (dd, 1H),7.34-7.32 (dt, 18), 7.15-7.11 (m, 1H), 6.89-6.83 (m, 1H), 6.65-6.60 (m,1H), 4.46-4.29 (m, 4H), 3.55-3.47 (m, 1H); MS (EI) for C₁₇H₁₂F₃IN₂O₃:477 (MH⁺).

Example 2N-[1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N2,N2-diethylglycinamide

A solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid(200 mg, 0.51 mmol), prepared using procedures similar to those in U.S.Pat. No. 7,019,033, PyBOP (256 mg, 0.51 mmol), commercially availabletert-butyl azetidin-3-ylcarbamate (131 mg, 0.77 mmol) andN,N-diisopropylethylamine (180 μL, 1.02 mmol) in dimethylformamide (3mL) was stirred at room temperature for 15 hours. The reaction mixturewas partitioned between 5% aqueous lithium chloride and ethyl acetate.The organic portion was washed with 20% aqueous citric acid, saturatedaqueous sodium bicarbonate, brine, dried over sodium sulfate, filteredand concentrated in vacuo to afford a brown residue which was purifiedby silica gel column chromatography eluting with 30% ethyl acetate inhexanes to afford 1,1-dimethylethyl[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate(225 mg, 80% yield) as a colorless oil. ¹H NMR (400 MHz, DMSO): 8.56 (s,1H), 7.60-7.55 (m, 2H), 7.38 (d, 1H), 7.30-7.26 (m, 1H), 7.20-7.13 (m,1H), 6.71-6.66 (m, 1H), 4.37-4.20 (m, 2H), 4.18-4.06 (m, 1H), 3.98-3.93(m, 1H), 3.82-3.75 (m, 1H), 1.37 (s, 9H). MS (EI) C₂₁H₂₁N₃O₃F₃I: 548(MH⁺).

A solution of 1,1-dimethylethyl[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate(113 mg, 0.20 mmol) and trifluoroacetic acid (500 μL) in dichloromethane(2 mL) was added stirred at room temperature for one hour then waspartitioned between saturated aqueous sodium bicarbonate, anddichloromethane. The organic portion was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated to afford acolorless residue which was purified by column chromatography elutingwith 10% methanol in dichloromethane to afford1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine(85 mg, 95% yield) as a white foam. ¹H NMR (400 MHz, CDCl₃): 8.53 (s,1H), 7.39 (d, 1H), 7.32 (d, 1H), 7.13-7.09 (m, 1H), 6.84-6.77 (m, 1H),6.63-6.57 (m, 1H), 4.46-4.39 (m, 2H), 3.98-3.75 (br m, 4H); MS (EI) forC₁₆H₁₃F₃IN₃O: 448 (MH⁺).

A solution of1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine(100 mg, 0.22 mmol), PyBOP (131 mg, 0.25 mmol),N,N-diisopropylethylamine (80 μL, 0.44 mol) and bromoacetic acid (35 mg,0.25 mmol) in dimethylformamide (1 mL) was stirred at room temperaturefor 15 hours. The reaction mixture was concentrated in vacuo and theresultant residue was purified by column chromatography eluting with 80%ethyl acetate in hexanes to afford2-bromo-N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]acetamide(102 mg, 82% yield) as a white foam. MS (EI) for C₁₈H₁₄BrF₃IN₃O₂: 568.

A solution of2-bromo-N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]acetamide(30 mg, 0.05 mmol) and N,N-diethylamine (100 μL, excess) indichloromethane (2 mL) was stirred at room temperature for 15 hours. Thereaction mixture was concentrated in vacuo and purified by preparativereverse phase HPLC (CH₃CN/H₂O with 0.1% TFA). Isolated product wasconcentrated in vacuo to affordN-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N2,N2-diethylglycinamidetrifluoroacetate salt (13.0 mg, 38% yield) as a white solid. ¹H NMR (400MHz, CDCl₃): 9.36 (br s, 1H), 9.25 (d, 1H), 8.60 (s, 1H), 7.60 (d, 1H),7.40 (d, 1H), 7.33-7.27 (m, 1H), 7.22-7.15 (m, 1H), 6.73-6.66 (m, 1H),4.54-4.40 (m, 2H), 4.25-4.20 (m, 1H), 4.04-3.82 (m, 4H), 3.17-3.12 (m,4H), 1.18-1.15 (m, 6H); MS (EI) C₂₂H₂₄F₃IN₄O₂: 561 (MH⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative reagents, the compounds in Examples 2(a)-(n) wereprepared.

Example 2(a)

1,1-Dimethylethyl[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate:¹H NMR (400 MHz, CDCl₃): 8.52 (br s, 1H), 7.40 (dd, 1H), 7.33 (dt, 1H),7.13-7.07 (m, 1H), 6.80 (ddd, 1H), 6.61 (ddd, 1H), 5.01-4.88 (br, 1H),4.55-4.37 (br, 4H), 4.05 (br d, 1H), 1.43 (s, 9H); MS (EI) forC₂₁H₂₁F₃IN₃O₃S: 548 (MH⁺).

Example 2(b)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-aminetrifluoroacetate salt: ¹H NMR (400 MHz, CDCl₃): 8.53 (s, 1H), 7.39 (d,1H), 7.32 (d, 1H), 7.13-7.09 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m,1H), 4.46-4.39 (m, 2H), 3.98-3.75 (br m, 4H); MS (EI) for C₁₆H₁₃F₃IN₃O:448 (MH⁺).

Example 2(c)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-2-methylpropanamide:¹H NMR (400 MHz, DMSO): 8.60 (s, 1H), 8.38 (d, 1H), 7.59 (d, 1H), 7.38(d, 1H), 7.32-7.28 (m, 1H), 7.18-7.13 (m, 1H), 6.72-6.66 (m, 1H),4.45-4.35 (m, 1H), 4.18-3.77 (m, 4H), 2.36-2.28 (m, 1H), 0.99 (d, 6H);MS (EI) C₂₀H₁₉F₃IN₃O₂: 518 (MH⁺).

Example 2(d)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]formamide:¹H NMR (400 MHz, DMSO): 8.69 (d, 1H), 8.58 (s, 1H), 8.02 (s, 1H), 7.59(d, 1H), 7.39 (d, 1H), 7.31-7.27 (m, 1H), 7.19-7.13 (m, 1H), 6.70-6.66(m, 1H), 4.55-4.46 (m, 1H), 4.42-4.36 (m, 1H), 4.20-4.16 (m, 1H),4.01-3.97 (m, 1H), 3.82-3.79 (m, 1H); MS (EI) C₁₇H₁₃F₃IN₃O₂: 476 (MH⁺).

Example 2(c)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-3,4-dihydroxybutanamide:¹H NMR (400 MHz, DMSO): 8.60 (s, 1H), 8.47 (d, 1H), 7.59 (d, 1H), 7.39(d, 1H), 7.31-7.28 (m, 1H), 7.20-7.14 (m, 1H), 6.72-6.66 (m, 1H),4.45-4.35 (m, 2H), 4.18-4.14 (m, 1H), 4.00-3.92 (m, 1H), 3.84-3.78 (m,2H), 3.31-3.18 (m, 2H), 2.38-2.18 (m, 1H), 2.09-2.03 (m, 1H); MS (EI)C₂₀H₁₉F₃IN₃O₄: 550 (MH⁺).

Example 2(f)

methyl[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate:¹H NMR (400 MHz, DMSO): 8.58 (s, 1H), 7.84 (d, 1H), 7.59 (d, 1H), 7.39(d, 1H), 7.35-7.27 (m, 1H), 7.20-7.13 (m, 1H), 6.71-6.66 (m, 1H),4.38-4.25 (m, 2H), 4.17-4.12 (m, 1H), 4.00-3.97 (m, 1H), 3.83-3.78 (m,1H), 3.53 (s, 3H); MS (EI) C₁₈H₁₅F₃IN₃O₃: 506 (MH⁺).

Example 2(g)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-2-(4-methylpiperazin-1-yl)acetamidetrifluoroacetate salt: ¹H NMR (400 MHz, DMSO): 8.64 (s, 1H), 8.54 (d,1H), 7.60 (d, 1H), 7.39 (d, 1H), 7.32-7.29 (m, 1H), 7.21-7.15 (m, 1H),6.72-6.66 (m, 1H), 4.54-4.28 (m, 2H), 4.19-4.15 (m, 1H), 4.06-4.00 (m,1H), 3.91-3.84 (m, 1H), 3.44-3.24 (m, 2H), 3.16-2.92 (m, 6H), 2.78 (s,3H), 2.62-2.50 (m, 2H); MS (EI) C₂₃H₂₅F₃IN₅O₂: 588 (MH⁺).

Example 2(h)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N,N-bis(2-hydroxyethyl)glycinamidetrifluoroacetate salt: ¹H NMR (400 MHz, DMSO): 9.19 (d, 1H), 7.60 (d,1H), 7.41 (d, 1H), 7.31-7.27 (m, 1H), 7.21-7.15 (m, 1H), 6.73-6.66 (m,1H), 4.51-4.40 (m, 2H), 4.23-4.18 (m, 1H), 4.05-3.98 (m, 3H), 3.86-3.82(m, 1H), 3.75-3.69 (m, 3H), 3.32 (br s, 4H) C₂₂H₂₄F₃IN₄O₄: 593 (MH⁺).

Example 2(i)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-2-piperidin-1-ylacetamidetrifluoroacetate salt: ¹H NMR (400 MHz, DMSO): 9.20 (d, 1H), 7.60 (d,1H), 7.41 (d, 1H), 7.31-7.27 (m, 1H), 7.21-7.15 (m, 1H), 6.73-6.66 (m,1H), 4.52-4.40 (m, 2H), 4.24-4.18 (m, 1H), 4.05-4.00 (m, 1H), 3.87-3.80(m, 3H), 3.40-3.32 (m, 2H), 3.00-2.91 (m, 2H), 1.82-1.66 (m, 6H); MS(EI) C₂₃H₂₄F₃IN₄O₂: 573 (MH⁺).

Example 2(j)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N3-(2-hydroxyethyl)-N3-methyl-beta-alaninamidehydrochloride: ¹H NMR (400 MHz, DMSO): 9.36 (br s, 1H), 8.86 (d, 1H),8.60 (s, 1H), 7.59 (d, 1H), 7.39 (d, 1H), 7.32-7.26 (m, 1H), 7.21-7.14(m, 1H), 6.72-6.66 (m, 1H), 5.35-5.33 (m, 1H), 4.48-4.37 (m, 2H),4.20-4.15 (m, 1H), 4.02-3.96 (m, 1H), 3.84-3.79 (m, 1H), 3.74-3.68 (m,2H), 3.42-3.06 (m, 4H), 2.75 (s, 3H), 2.65-2.60 (m, 2H); MS (EI)C₂₂H₂₄F₃IN₄O₃: 577 (MH⁺).

Example 2(k)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N3,N3-bis(2-hydroxyethyl)-beta-alaninamidehydrochloride: ¹H NMR (400 MHz, DMSO): 9.39 (br s, 1H), 8.91 (d, 1H),8.61 (s, 1H), 7.59 (d, 1H), 7.39 (d, 1H), 7.31-7.27 (m, 1H), 7.21-7.14(m, 1H), 6.72-6.66 (m, 1H), 5.31 (br s, 21H), 4.46-4.36 (m, 2H),4.20-4.15 (m, 1H), 4.02-3.97 (m, 1H), 3.85-3.72 (m, 5H), 3.30-3.17 (m,4H), 2.68-2.63 (m, 2H); MS (EI) C₂₃H₂₆F₃IN₄O₄: 607 (MH⁺).

Example 2(m)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N2-methylglycinamidetrifluoroacetate salt: ¹H NMR (400 MHz, DMSO): 9.09 (d, 1H), 8.69 (br s,2H), 8.60 (s, 1H), 7.60 (d, 1H), 7.39 (d, 1H), 7.31-7.27 (m, 1H),7.22-7.15 (m, 1H), 6.73-6.66 (m, 1H), 4.54-4.41 (m, 2H), 4.25-4.19 (m,1H), 3.99-3.96 (m, 1H), 3.84-3.78 (m, 1H), 3.72-3.67 (m, 2H), 2.58-2.54(m, 3H); MS (EI) C₁₉H₁₈F₃IN₄O₂: 519 (MH⁺).

Example 2(n)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]glycinamidetrifluoroacetate salt: ¹H NMR (400 MHz, DMSO): 8.59 (s, 1H), 8.46 (br s,1H), 7.59 (d, 1H), 7.39 (d, 1H), 7.32-7.28 (m, 1H), 7.20-7.13 (m, 1H),6.72-6.66 (m, 1H), 4.49 (br s, 1H), 4.40-4.35 (m, 1H), 4.18-4.13 (m,1H), 4.05-4.01 (m, 1H), 3.86-3.81 (m, 1H), 3.07 (s, 2H); MS (EI)C₁₈H₁₆F₃IN₄O₂: 505 (MH⁺).

Example 31-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(morpholin-4-ylmethyl)azetidin-3-ol

A mixture of 3-azetidinol hydrochloride (10 g, 91 mmol), di-tert-butyldicarbonate (18.8 g, 86.3 mmol) and sodium bicarbonate (15.3 g, 182mmol) in dioxane:water (400 mL, 1:1) was stirred at room temperature for15 hours. The organic portion was removed in vacuo and the aqueousportion was extracted with ethyl acetate three times. The combinedorganic portion was washed with 5% aqueous HCl, water, brine, dried oversodium sulfate, filtered and concentrated in-vacuo to afford 12.8 g, 74mmol (81%) of 1,1-dimethylethyl 3-hydroxyazetidine-1-carboxylate as acolorless oil without further purification. ¹H NMR (400 MHz, DMSO): 5.62(d, 1H), 4.40-4.33 (m, 1H), 4.02-3.95 (m, 2H), 3.62-3.54 (m, 2H), 1.37(s, 9H). GC/MS for C₈H₁₅NO₃: 173.

A solution of oxalyl chloride (545 μL, 6.36 mmol) in dichloromethane (25mL) was cooled to −78° C. While maintaining an internal temperature of−78° C., the dropwise addition of DMSO (903 μL, 12.7 mmol) followed by1,1-dimethylethyl 3-hydroxyazetidine-1-carboxylate (1 g, 5.78 mmol in 30mL of dichloromethane) and finally triethylamine (3.25 mL, 23.1 mmol in20 mL of dichloromethane) was performed. The mixture was allowed to warmto room temperature and was stirred for 15 hours. The reaction mixturewas diluted with water and partitioned and the organic portion waswashed twice with water. The combined aqueous portion was extracted oncewith dichloromethane. The combined organic portion was washed withbrine, dried over sodium sulfate, filtered and concentrated in vacuo toafford a yellow oil which was purified by column chromatography. Elutingwith 30% ethyl acetate in hexanes, isolated product was concentrated invacuo to afford 893 mg, 5.20 mmol (90%) of 1,1-dimethylethyl3-oxoazetidine-1-carboxylate as a colorless oil, which solidified uponstanding. ¹H NMR (400 MHz, DMSO): 4.67 (s, 4H), 1.42 (s, 9H). GC/MS forC₈H₁₃NO₃: 171.

A mixture of potassium tert-butoxide (15.5 g, 137 mmol) andmethyltriphenylphosphine bromide (49 g, 137 mmol) in diethyl ether (300mL) was stirred at room temperature for 1 hour, followed by the additionof 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (10 g, 58 mmol in 100mL diethyl ether). The mixture was stirred at 35° C. for 2 hours andthen allowed to cool to room temperature. The mixture was filteredthrough a pad of celite, washing with diethyl ether. The filtrate waspartitioned with water and washed twice with water, brine, dried oversodium sulfate, filtered and concentrated in vacuo to give an orange oilwhich was purified by column chromatography. Eluting with 10% ethylacetate in hexanes, isolated product was concentrated in vacuo to afford9.80 g, 58 mmol (100%) of 1,1-dimethylethyl3-methylideneazetidine-1-carboxylate as a colorless oil. ¹H NMR (400MHz, DMSO): 5.05-4.85 (m, 2H), 4.95-4.63 (m, 4H), 1.45 (s, 9H). GC-MSfor C₉H₁₅NO₂: 169.

To a solution of 1,1-dimethylethyl 3-methylideneazetidine-1-carboxylate(2.96 g, 17.5 mmol) in chloroform (180 mL) was added3-chloroperoxybenzoic acid (77%, 13.9 g, 62.0 mmol), and the resultingmixture was stirred at room temperature for 2 days. The reaction mixturewas quenched with a 1:1 mixture (150 mL) of 10% sodium thiosulfate andsaturated sodium bicarbonate solutions. The organic portion wasisolated, dried over sodium sulfate, filtered and concentrated to givean oily residue which was then purified by flash chromatography (15-50%ethyl acetate-hexanes) to give 1,1-dimethylethyl1-oxa-5-azaspiro[2,3]hexane-5-carboxylate (1.65 g, 51%), GC-MS forC₉H₁₅NO₃: 185.

1,1-Dimethylethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (51 mg, 0.28mmol) was taken into THF (1 mL) followed by addition of morpholine (123μL, 1.4 mmol) and the mixture was stirred for one hour at roomtemperature. The solution was then concentrated and the residuepartitioned with ethyl acetate and water. The organic layer was washedonce with water then brine and the organic layer dried over anhydroussodium sulfate. Filtration and concentration gave a colorless oil thatwas purified by silica gel flash chromatography using ethyl acetate to10% methanol in dichloromethane as eluents. The combined pure fractionswere concentrated and the residue treated with neat TFA (1 mL) for 5minutes then concentrated. The residue was taken into methanol (2 mL)and basified to pH >10 by addition of Biorad AG-IX hydroxide form resin.Filtration and concentration afforded3-(morpholin-4-ylmethyl)azetidin-3-ol (11.6 mg, 24% yield) as acolorless oil. ¹H NMR (400 MHz, CD₃OD): 3.69-3.66 (m, 4H), 3.55 (d, 2H),3.49 (d, 2H), 2.66 (s, 2H), 2.57-2.55 (m, 4H).

3-(Morpholin-4-ylmethyl)azetidin-3-ol (11.6 mg, 0.07 mmol) was takeninto DMF (1 mL) followed by addition of DIPEA (35 μL, 0.21 mmol) and3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (28 mg,0.07 mmol), prepared using procedures similar to those described inReference 1, and the mixture was stirred for 30 minutes at roomtemperature. The solution was then concentrated in vacuo and the residuepurified by preparative reverse phase HPLC. Lyophillization of thecombined fractions gave1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(morpholin-4-ylmethyl)azetidin-3-oltrifluoroacetate salt (6.3 mg) as a colorless amorphous solid. ¹H NMR(400 MHz, CD₃OD): 7.48 (d, 1H), 7.36 (d, 1H), 7.33-7.29 (m, 1H),7.08-7.02 (m, 1H), 6.65-6.60 (m, 1H), 4.39 (br d, 1H), 4.24-4.18 (br,2H), 4.08-3.96 (br m, 3H), 3.80 (br s, 2H), 3.51 (d, 2H), 3.40 (br s,2H), 3.24 (br s, 2H).

Using the same or analogous synthetic techniques and substituting, asnecessary, with alternative reagents, the following compounds wereprepared.

Example 3(a)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(pyrrolidin-1-ylmethyl)azetidin-3-ol:MS (EI) for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺).

Example 3(b)

1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}piperidin-4-ol:MS (EI) for C₂₂H₂F₃IN₃O₃: 562 (MH⁺).

Example 3(c)

3-{[bis(2-hydroxyethyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:MS (EI) for C₂₁H₂₂F₃IN₃O₄: 566 (MH⁺).

Example 3(d)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(4-methylpiperazin-1-yl)methyl]azetidin-3-ol:MS (EI) for C₂₂H₂F₃IN₄O₂: 561 (MH⁺).

Example 3(e)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(4-methyl-1,4-diazepan-1-yl)methyl]azetidin-3-ol:MS (EI) for C₂₃H₂₆F₃N₄O₂: 575 (MH⁺).

Example 3(f)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[methyl(1-methylpyrrolidin-3-yl)amino]methyl}azetidin-3-ol:MS (EI) for C₁₃H₂₆F₃IN₄O₂: 575 (MH⁺).

Example 3(g)

3-(1,4′-bipiperidin-1′-ylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:MS (EI) for C₂₇H₃₂F₃IN₃O₂: 629 (MH⁺).

Example 3(h)

3-({4-[2-(diethylamino)ethyl]piperazin-1-yl}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:MS (EI) for C₂₇H₃₅F₃IN₃O₂: 647 (MH⁺).

Example 3(i)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxyethylmethyl)amino]methyl}azetidin-3-ol:MS (EI) for C₂₀H₂₁F₃IN₃O₃: 536 (MH⁺).

Example 3(j)

3-(azetidin-1-ylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:MS (EI) for C₂₀H₃₉F₃IN₃O₂: 518 (MH⁺).

Example 3(k)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-methylethyl)amino]methyl}azetidin-3-ol:MS (EI) for C₂₀H₂₁F₃IN₃O₂: 520(MH⁺).

Example 3(m)

3-(aminomethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:MS (EI) for C₁₇H₁₅F₃IN₃O₂: 478 (MH⁺).

Example 3(n)

N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}acetamide:MS (EI) for C₁₉H₁₇F₃IN₃O₃: 520 (MH⁺).

Example 3(o)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1,1-dimethylethyl)amino]methyl}azetidin-3-ol:MS (EI) for C₂₁H₂₃F₃IN₃O₄: 534 (MH⁺).

Example 3(q)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(hydroxyamino)methyl]azetidin-3-ol:¹H NMR (400 MHz, d₄-MeOH): 7.45 (2d, 1H), 7.35 (m, 1H), 7.28 (m, 1H),7.03 (m, 1H), 6.63 (m, 1H), 4.32 (d, 1H), 4.05 (dd, 2H), 3.85 (d, 1H),3.00 (s, 2H); MS (EI) for C₁₇H_(1S)F₃IN₃O₃: 494 MH⁺).

Example 3(r)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(methyloxy)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, d₄-MeOH): 7.45 (2d, 1H), 7.35 (m, 1H), 7.27 (m, 1H),7.04 (m, 1H), 6.62 (m, 1H), 4.26 (d, 1H), 4.08 (d, 1H), 4.00 (d, 1H),3.84 (d, 1H), 3.30 (s, 3H), 3.00 (d, 2H); MS (EI) for C₁₈H₁₇F₃IN₃O₃: 508(MH⁺).

Example 3(s)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(ethyloxy)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, d₄-MeOH): 7.45 (2d, 1H), 7.34 (m, 1H), 7.26 (m, 1H),7.03 (m, 1H), 6.63 (m, 1H), 4.26 (d, 1H), 4.12 (d, 1H), 4.00 (d, 1H),3.84 (d, 1H), 3.61 (dd, 2H), 3.00 (s, 2H), 1.06 (t, 3H); MS (EI) forC₁₉H₁₉F₃IN₃O₃: 522 (MH⁺).

Example 3(t)

1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}guanidineacetate salt: ¹H NMR (400 MHz, d₄-MeOH): 7.46 (2d, 1H), 7.36 (m, 1H),730 (m, 1H), 7.04 (m, 1H), 6.62 (m, 1H), 4.18 (d, 1H), 4.08 (d, 1H),4.02 (d, 1H), 3.88 (1H), 3.40 (s, 2H); MS (EI) for C₁₈H₁₇F₃INO₂: 520(MH⁺).

Example 3(u)

N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}benzenecarboximidamidehydrochloride: ¹H NMR (400 MHz, d₄-MeOH): 7.70 (d, 3H), 7.58 (m, 2H),7.46 (dd, 1H), 7.36 (m, 1H), 7.31 (m, 1H), 7.04 (m, 1H), 6.62 (m, 1H),4.28 (m, 1H), 4.15 (m, 2H), 3.96 (m, 1H), 3.78 (s, 2H); MS (EI) forC₂₄H₂₀F₃IN₄O₂: 581 (MH⁺).

Example 3(v)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(pyrimidin-2-ylamino)methyl]azetidin-3-olhydrochloride: ¹H NMR (400 MHz, d₄-MeOH): 8.48 (s, 2H), 7.46 (2d, 1H),7.36 (m, 1H), 7.28 (m, 1H), 7.04 (m, 1H), 6.85 (t, 1H), 6.61 (m, 1H),4.24 (d, 1H), 4.06 (t, 2H), 3.87 (d, 1H), 3.75 (d, 2H); MS (EI) forC₂₁H₁₇F₃IN₅O₂: 556 (M⁺).

Example 3(w)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(pyridin-2-ylamino)methyl]azetidin-3-olhydrochloride: ¹H NMR (400 MHz, d₄-MeOH): 7.87 (dd, 1H), 7.85 (dd, 1H),7.46 (2d, 1H), 7.36 (m, 2H), 7.06 (m, 2H), 6.89 (m, 1H), 6.61 (m, 1H),4.53 (d, 2H), 4.46 (m, 1H), 4.28 (m, 1H), 4.16 (m, 1H), 3.96 (m, 1H); MS(EI) for C₂₂H₁₈F₃IN₄O₂: 555 (MH⁺).

Example 3(x)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(ethylamino)methyl]azetidin-3-ol:¹H NMR (400 MHz, de-DMSO): 8.61 (s, 21H), 7.59 (d, 1H), 7.40 (d, 1H),7.36-7.33 (m, 1H), 7.23-7.18 (m, 1H), 6.71 (s, 2H); 4.31-4.26 (m, 1H),4.13-4.05 (m, 2H), 3.88-3.84 (m, 1H), 3.21 (br m, 2H), 2.97-2.90 (m,2H), 1.19 (t, 3H). MS (EI) for C₁₉H₁₉F₃IN₃O₂: 506 (MH⁺).

Example 3(y)

3-[(cyclopropylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.99 (br s, 2H), 8.60 (s, 1H), 7.58 (d, 1H),7.39 (d, 1H), 7.36-7.33 (m, 1H), 7.23-7.16 (m, 1H), 6.72 (s, 2H),4.34-4.29 (m, 1H), 4.14-4.04 (m, 2H), 3.88-3.84 (m, 1H), 2.70-2.64 (m,1H), 0.89 (br s, 2H), 0.74-0.69 (br s, 21H). MS (EI) for C₂₀H₁₉F₃IN₃O₂:518 (MH⁺).

Example 3(z)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2,2,2-trifluoroethyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.60 (s, 1H), 7.58 (d, 1H), 7.38 (d, 1H),7.35-7.30 (m, 1H), 7.22-7.17 (m, 1H), 6.72-6.67 (m, 1H), 4.25-4.19 (m,1H), 4.07-3.98 (m, 2H), 3.86-3.77 (m, 2H), 3.19-3.09 (m, 2H). MS (EI)for C₁₉H₁₆F₆IN₃O₂: 560 (MH⁺).

Example 3(Aa)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1H-1,2,3-triazol-1-ylmethyl)azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.55 (s, 1H), 8.04 (s, 1H), 7.66 (s, 1H),7.58 (d, 1H), 7.39 (d, 1H), 7.34-7.29 (m, 1H), 7.22-7.15 (m, 1H),6.72-6.66 (m, 1H), 6.29 (s, 1H), 4.64 (s, 2H), 4.29-4.25 (m, 1H),4.13-4.09 (m, 1H), 4.00-3.96 (m, 1H), 3.77-3.73 (m, 1H), 3.16 (d, 1H).MS (EI) for C₁₉H₁₅F₃IN₅O₂: 530 (MH⁺).

Example 3(bb)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2,2-dimethylpropyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.61 (s, 1H), 8.30 (s, 2H), 7.59 (d, 1H),7.39 (d, 1H), 7.36-7.17 (m, 4H), 6.77-6.66 (m, 4H), 4.35-4.30 (m, 1H),4.16-4.08 (m, 2H), 3.92-3.87 (n, 1H), 3.31-3.27 (m, 2H), 2.78-2.74 (m,2H), 1.76 (s, 4H), 0.99 (s, 91). MS (EI) for C₂₂H₂₅F₃IN₃O₂: 548 (MH⁺).

Example 3(cc)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(4-methylphenyl)ethyl]amino}methyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CDCl₃): 8.48 (s, 1H), 7.39 (dd, 1H),7.31-7.34 (m, 1H), 7.08 (dd, 51H), 6.77-6.83 (m, 1H), 6.58-6.63 (m, 1H),4.20 (br s, 1H), 4.01 (d, 1H), 2.87 (t, 4H), 2.75 (t, 41H), 2.5 (br s,2H), 2.33 (s, 3H), 2.08 (s, 2H). MS (EI) for C₂₆H₂F₃IN₃O₂: 594 (MH⁺).

Example 3(dd)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2,3-dihydro-1H-inden-2-ylamino)methyl]azetidin-3-olacetate salt: ¹H NMR (400 MHz, CDCl₃): 8.48 (s, 1H), 7.40 (dd, 1H),7.32-7.34 (m, 1H), 7.15-7.22 (m, 4H), 7.10-7.14 (m, 1H), 6.77-6.83 (m,1H), 6.58-6.64 (m, 1H), 4.22 (br s, 1H), 4.04 (d, 1H), 3.57-3.63 (m,1H), 3.17 (dd, 2H), 2.94 (s, 2H), 2.75 (dd, 2H), 2.48 (br s, 4H), 2.08(s, 2H). MS (EI) for C₂₆H₂₃F₃IN₃O₂: 592 (M-H).

Example 3(ee)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1S,2S)-2-hydroxycyclopentyl]amino}methyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.46 (dd, 1H), 7.33-7.37 (m, 1H),7.26-7.31 (m, 1H), 7.00-7.08 (m, 1H), 6.58-6.65 (m, 1H), 4.2 (t, 1H),3.86-4.06 (m, 4H), 2.92-3.10 (m, 3H), 2.00-2.10 (m, 1H), 1.91-1.97 (m,3H), 1.66-1.78 (m, 2H), 1.52-1.61 (m, 1H), 1.32-1.44 (m, 1H). MS (EI)for C₂₂H₂₃F₃IN₃O₃: 560 (M-H).

Example 3(ff)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1,2-dimethylpropyl)amino]methyl}azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.45 (dd, 1H), 7.33-7.37 (m, 1H),7.26-7.31 (m, 1H), 7.01-7.08 (m, 1H), 6.59-6.64 (m, 1H), 4.14-4.22 (m,1H), 3.98-4.06 (m, 2H), 3.84-3.90 (m, 1H), 2.86-3.20 (m, 2H), 2.65 (brs, 1H), 1.92 (s, 2H), 1.76-1.86 (m, 1H), 1.06 (d, 3H), 0.91 (dd, 6H). MS(EI) for C₂₂H₂₅F₃I N₃O₂: 546 (M-H).

Example 3(gg)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[1-methy-2-(methyloxy)ethyl]amino}methyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.55 (dd, 1H), 7.33-7.36 (m, 1H),7.26-7.31 (m, 1H), 7.01-7.09 (m, 1H), 6.59-6.65 (m, 1H), 4.14-4.22 (m,1H), 3.96-4.06 (m, 2H), 3.85-3.92 (m, 1H), 3.40-3.48 (m, 1H), 3.34 (s,3H), 2.90-3.15 (m, 3H), 1.94 (s, 3H), 1.11 (d, 3H). MS (EI) forC₂₁H₂₃F₃IN₃O₃: 548 (M-H).

Example 3(hh)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-ethylpropyl)amino]methyl}azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.45 (dd, 1H), 7.33-7.36 (m, 1H),7.26-7.31 (m, 1H), 7.01-7.09 (m, 1H), 6.58-6.65 (m, 1H), 4.15-4.20 (m,1H), 3.99-4.06 (m, 2H), 3.86-3.91 (m, 1H), 2.94 (s, 21H), 2.55-2.63 (m,1H), 1.92 (s, 2H), 1.48-1.58 (m, 4H), 0.92 (t, 6H). MS (EI) forC₂₂H₂₅F₃IN₃O₂: 546 (M-H).

Example 3(ii)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1H-imidazol-1-ylmethyl)azetidin-3-ol:¹H NMR (400 MHz, CD₃OD): 7.67 (br s, 1H), 7.48 (m, 1H), 7.36 (m, 1H),6.91 (br s, 1H), 6.63 (m, 1H), 4.25 (s, 2H), 4.22 (m, 1H), 4.02 (m, 2H),3.82 (m, 1H). MS (EI) for C₂₀H₁₆F₃IN₄O₂: 529 (MH⁺).

Example 3(jj)

3-{[(cyclopropylmethyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:¹H NMR (400 MHz, CD₃OD): 7.47 (m, 1H), 7.36 (m, 1H), 7.31 (m, 1H), 7.05(m, 1H), 6.62 (m, 1H), 4.30 (m, 1H), 4.24 (m, 21H), 3.99 (m, 1H), 3.66(m, 2H), 2.91 (d, 2H), 1.08 (m, 1H), 0.71 (m, 2H), 0.40 (m, 2H). MS (EI)for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺).

Example 3(kk)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(phenylmethyl)amino]methyl}azetidin-3-olhydrochloride: ¹H NMR (400 MHz, CD₃OD): 7.47 (m, 5H), 7.43 (m, 1H), 7.35(m, 1H), 7.27 (m, 1H), 7.04 (m, 1H), 6.61 (m, 1H), 4.24 (m, 3H), 4.08(m, 2H), 3.96 (m, 1H). MS (EI) for C₂₄H₂₁F₃IN₃O₂: 568 (MH⁺).

Example 3(mm)

3-[(butylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.56 (s, 1N), 7.57 (dd, 1H), 7.36 (d, 1H),7.31 (t, 1H), 7.17 (q, 1H), 6.67 (dt, 1H), 4.04 (d, 1H), 3.88 (q, 2H),3.69 (d, 1H), 2.59 (s, 2H), 1.90 (s, 2H), 1.22-1.33 (m, 4H), 0.84 (t,3H); MS (EI) for C₂₁H₂₃F₃IN₃O₂: 534 (MH⁺).

Example 3(nn)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1-ethylpyrrolidin-2-yl)methyl]amino}methyl)azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.59 (s, 1H), 7.57 (dd, 1H), 7.36 (d, 1H),7.31 (t, 1H), 7.17 (q, 1H), 6.68 (dt, 1H), 4.02 (t, 1H), 3.89 (q, 2H),3.69 (d, 1H), 2.98 (s, 1H), 2.67-2.76 (m, 1H), 2.62 (s, 1H), 2.39-2.45(m, 1H), 2.29 (s, 1H), 1.97-2.13 (m, 2H), 1.69 (s, 1H), 1.54 (s, 3H),0.97 (t, 3H); MS (EI) for C₂₄H₂₈F₃IN₄O₂: 589 (MH⁺).

Example 3(oo)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxyethyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.57 (s, 1H), 7.57 (dd, 1H), 7.37 (d, 1H),7.32 (t, 1H), 7.18 (q, 1H), 6.68 (dt, 1H), 4.06 (d, 1H), 3.87 (d, 2H),3.70 (d, 1H), 3.42 (t, 2H), 2.65 (s, 2H), 2.56 (dt, 2H), 1.91 (s, 2H);MS (EI) for C₁₉H₁₉F₃IN₃O₃: 522 (MH⁺).

Example 3(pp)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(dimethylamino)ethyl]amino}methyl)azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.58 (s, 1H), 7.57 (dd, 1H), 7.36 (d, 1H),7.31 (t, 1H), 7.17 (q, 1H), 6.68 (dt, 1H), 4.02 (d, 1H), 3.87 (t, 2H),3.70 (d, 1H), 2.62 (s, 1H), 2.54 (t, 1H), 2.23 (t, 1H), 2.09 (s, 4H),7.85 (s, 6H); MS (EI) for C₂₁H₂₄F₃IN₄O₂: 549 (MH⁺).

Example 3(qq)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(1-methylpyrrolidin-2-yl)ethyl]amino}methyl)azetidin-3-ol:¹H NMR (400 MHz, d-DMSO): 8.58 (s, 1H), 7.57 (dt, 1H), 7.36 (d, 1H),7.31 (t, 1H), 7.17 (q, 1H), 6.68 (dt, 1H), 4.04 (d, 1H), 3.89 (d, 2H),3.79 (d, 1H), 2.88-2.92 (m, 1H), 2.61 (s, 2H), 2.15 (s, 3H), 1.93-2.04(m, 2H), 1.75-1.83 (m, 3H), 1.54-1.70 (m, 3H), 1.20-1.37 (m, 2H); MS(EI) for C₂₄H₂₈F₃IN₄O₂: 589 (MH⁺).

Example 3(rr)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(tetrahydrofuran-2-ylmethyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.58 (s, 1H), 7.57 (dd, 1H), 7.37 (d, 1H),7.31 (t, 1H), 7.14 (q, 1H), 6.68 (dt, 1H), 5.75 (s, 1H), 4.03 (t, 1H),3.87 (t, 2H), 3.76 (q, 1H), 3.68 (q, 2H), 3.54-3.58 (m, 1H), 2.63 (s,2H), 1.91 (s, 2H), 1.71-1.87 (m, 3H), 1.40-1.48 (m, 1H); MS (EI) forC₂₂H₂₃F₃IN₃O₃: 562 (MH⁺).

Example 3(ss)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3-pyrrolidin-1-ylpropyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.58 (s, 1H), 7.57 (dd, 1H), 7.36 (d, 1H),7.31 (t, 1H), 7.17 (q, 1H), 6.68 (dt, 1H), 4.04 (d, 1H), 3.89 (d, 2H),3.69 (d, 1H), 2.60 (s, 1H), 2.34-2.37 (m, 4H), 1.86 (s, 8H), 1.64 (s,2H), 1.46-1.53 (m, 1H); MS (EI) for C₂₄H₂₅F₃IN₄O₂: 589 (MH⁺).

Example 3(tt)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(methyloxy)ethyl]amino}methyl)azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): ¹H NMR (400 MHz, d₆-DMSO): 8.57 (s, 1H), 7.57(dd, 1H), 7.37 (d, 1H), 7.31 (t, 1H), 7.17 (q, 1H), 6.68 (dt, 1H), 4.03(d, 1H), 3.86 (d, 2H), 3.70 (d, 1H), 3.21 (s, 3H), 2.63 (s, 4H), 1.88(s, 2H); MS (EI) for C₂₀H₂₁F₃IN₃O₃: 536 (MH⁺).

Example 3(uu)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1-methylpiperidin-4-yl)methyl]amino}methyl)azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.58 (s, 1H), 7.57 (d, 1H), 7.37 (d, 1H),7.31 (t, 1H), 7.17 (q, 1H), 6.68 (t, 1H), 4.03 (d, 1H), 3.89 (t, 2H),3.69 (d, 1H), 2.68 (d, 2H), 2.57 (s, 1H), 2.34 (d, 2H), 1.88 (s, 4H),1.73 (t, 2H), 1.57 (d, 2H), 1.23 (s, 1H), 1.05 (q, 2H); MS (EI) forC₂₄H₂₈F₃IN₄O₃: 589 (MH⁺).

Example 3(w)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[4-(dimethylamino)butyl]amino}methyl)azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 7.57 (dd, H), 7.36 (d, 1H), 7.31 (t, 1H),7.18 (q, 1H), 6.68 (dt, 1H), 4.03 (t, 2H), 3.88 (t, 2H), 3.70 (d, 1H),3.08 (s, 1H), 2.60 (s, 1H), 2.44-2.47 (m, 21H), 2.28-2.33 (m, 1H),2.07-2.16 (m, 6H), 1.29-1.35 (m, 4H); MS (EI) for C₂₃H₂₈F₃IN₄O₂: 577(MH⁺).

Example 3(ww)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-furan-2-ylethyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.58 (s, 1H), 7.57 (d, 1H), 7.49 (s, 1H),7.36 (d, 1H), 7.31 (t, 1H), 7.17 (q, 1H), 6.68 (t, 1H), 6.33 (s, 1H),6.08 (s, 1H), 5.72 (s, 1H), 4.04 (d, 1H), 3.87 (d, 2H), 3.70 (d, 1H),2.74 (d, 2H), 2.69 (d, 2H), 2.64 (s, 2H); MS (EI) for C₂₃H₂₁F₃IN₃O₃: 572(MH⁺).

Example 3(xx)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-ethylbutyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, d-DMSO): 8.58 (s, 1H), 7.56 (dd, 1H), 7.36 (d, 1H),7.31 (t, 1H), 7.17 (q, 1H), 6.67 (dt, 1H), 4.03 (d, 1H), 3.90 (d, 2H),3.69 (d, 1H), 2.58 (s, 2H), 2.37 (d, 2H), 1.17-1.27 (m, 5H), 0.78 (t,6H); MS (EI) for C₂₃H₂₇F₃IN₃O₂: 562 (MH⁺).

Example 3(yy)

1,1-dimethylethyl[3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)propyl]carbamate:¹H NMR (400 MHz, d₆-DMSO): 8.58 (s, 1H), 7.57 (d, 1H), 7.30-7.38 (m,3H), 7.17 (q, 1H), 6.82 (t, 1H), 6.68 (dt, 1H), 4.07 (d, 1H), 3.89 (d,2H), 3.70 (d, 1H), 3.36 (s, 2H), 2.93 (q, 2H), 2.61 (s, 2H), 1.46 (t,2H), 1.36 (s, 9H); MS (EI) for C₂₅H₃₀F₃IN₄O₄: 635 (MH⁺).

Example 3(zz)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(pyrrolidin-2-ylmethyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.53 (s, 1H), 7.58 (dd, 1H), 7.37 (d, 1H),7.33 (d, 1H), 7.18 (q, 1H), 6.67 (dt, 1H), 6.25 (s, 1H), 4.07 (d, 1H),3.96 (q, 2H), 3.78 (s, 3H), 3.34 (s, 6H), 1.73 (s, 1H), 1.35-1.39 (m,1H); MS (EI) for C₂₂H₂₄F₃IN₄O₂: 561 (MH⁺).

Example 3(aa)

1,1-dimethylethyl4-[({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)methyl]piperidine-1-carboxylate:¹H NMR (400 MHz, d₆-DMSO): 8.56 (s, 1H), 7.56 (dd, 1H), 7.36 (d, 1H),7.30 (t, 1H), 7.17 (q, 1H), 6.68 (dt, 1H), 4.03 (d, 1H), 3.88 (t, 4H),3.69 (d, 1H), 2.58 (s, 2H), 2.35 (d, 2H), 1.60 (d, 2H), 1.47 (s, 1H),1.39 (s, 10H), 0.90 (q, 2H); MS (EI) for C₂₈H₃₄F₃IN₄O₄: 675 (MH⁺).

Example 3(bbb)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(2-hydroxyphenyl)methyl]amino}methyl)azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.56 (s, 1H), 7.54 (dd, 1H), 7.35 (d, 1H),7.30 (t, 1H), 7.17 (q, 1H), 7.05 (t, 2H), 6.64-6.72 (m, 3H), 4.07 (d,1H), 3.90 (t, 2H), 3.78 (s, 2H), 3.72 (d, 1H), 2.65 (s, 2H); MS (EI) forC₂₄H₂₁F₃IN₃O₃: 584 (M⁺).

Example 3(ccc)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(3-hydroxyphenyl)methyl]amino}methyl)azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.58 (s, 1H), 7.56 (d, 1H), 7.35 (d, 1H),7.29 (t, 1H), 7.16 (q, 1H), 7.06 (t, 1H), 6.64-6.72 (m, 3H), 6.60 (dd,1H), 4.07 (d, 1H), 3.88 (t, 2H), 3.69 (d, 1H), 3.60 (s, 2H), 2.58 (d,2H); MS (EI) for C₂₄H₂₁F₃IN₃O₃: 584 (MH⁺).

Example 3(ddd)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(4-hydroxyphenyl)methyl]amino}methyl)azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.57 (s, 1H), 7.55 (dd, 1H), 7.35 (d, 1H),7.27 (t, 1H), 7.16 (q, 1H), 7.06 (d, 2H), 6.64-6.70 (m, 3H), 4.04 (d,1H), 3.85 (t, 2H), 3.68 (d, 1H), 3.55 (s, 2H), 2.56 (d, 2H); MS (EI) forC₂₄H₂₁F₃IN₃O₃: 584 (MH⁺).

Example 3(eee)

3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)-5-(hydroxymethyl)cyclopentane-1,2-diol:¹H NMR (400 MHz, d-DMSO): 8.60 (broad s, 1H), 7.57 (dd, 1H), 7.37 (d,1H), 7.32 (t, 1H), 7.16 (q, 1H), 6.68 (t, 1H), 4.06 (q, 2H), 3.86 (t,3H), 3.72 (dd, 1H), 3.60 (t, 1H), 3.36-3.43 (m, 2H), 3.30 (dd, 1H), 2.80(q, 1H), 2.62-2.72 (m, 2H), 1.88-1.95 (m, 1H), 0.82-0.90 (m, 1H); MS(EI) for C₂₃H₃₅F₃IN₃O₅: 608 (MH⁺).

Example 3(fff)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(piperidin-4-ylmethyl)amino]methyl}azetidin-3-ol:H NMR (400 MHz, d₆-DMSO): 8.59 (broad s, 1H), 7.57 (dd, 1H), 7.37 (d,1H), 7.30 (t, 1H), 7.17 (q, 1H), 6.68 (dt, 1H), 4.03 (d, 1H), 3.87 (d,2H), 3.69 (d, 1H), 3.01 (d, 2H), 2.59 (s, 2H), 2.43-2.56 (m, 1H), 2.35(d, 2H), 1.65 (d, 2H), 1.47 (s, 1H), 1.07 (q, 2H); MS (EI) forC₂₃H₂₆F₃IN₄O₂: 575 (MH⁺).

Example 3(ggg)

3-{[(3-aminopropyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 7.57 (dd, 1H), 7.37 (d, 1H), 7.31 (t, 1H),7.17 (q, 1H), 6.68 (dt, 1H), 4.05 (d, 1H), 3.88 (d, 21H), 3.69 (d, 1H),2.61 (t, 3H), 2.53-2.56 (m, 1H), 1.49 (t, 1.49); MS (EI) forC₂₃H₂₆F₃IN₄O₂: 535 (MH⁺).

Example 3(hhh)

1-({³,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[({[2-(4-methylpiperazin-1-yl)phenyl]methyl}amino)methyl]azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.59 (broad s, 1H), 7.55 (dd, 1H), 7.34 (t,2H), 7.28 (d, 1H), 7.13-7.20 (m, 1H), 7.05 (d, 1H), 6.99 (t, 1H), 6.66(dt, 1H), 4.03 (d, 1H), 3.90 (t, 2H), 3.71 (d, 3H), 2.83 (s, 5H), 2.60(s, 2H), 2.42 (s, 3H), 2.20 (s, 3H); MS (EI) for C₂₉H₃₁F₃IN₅O₂: 666(MH⁺).

Example 3(iii)

3-[(1H-benzimidazol-2-ylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.04 (s, 2H), 7.28-7.35 (m, 2H), 7.23-7.26 (m,2H), 7.09-7.12 (m, 2H), 6.80 (q, 1H), 6.57-6.63 (m, 1H), 5.28 (broad s,2H), 4.38 (s, 3H), 4.25 (s, 1H), 4.21 (d, 2H); MS (EI) forC₂₄H₁₉F₃IN₅O₂: 594 (MH⁺).

Example 3(jjj)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1H-imidazol-2-ylamino)methyl]azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 12.12 (s, 1H), 8.68 (s, 1H), 7.57-7.61 (m,3H), 7.36-7.41 (m, 2H), 7.19 (q, 1H), 6.99 (s, 1H), 6.91 (s, 1H), 6.71(dt, 1H), 6.45 (s, 1H), 4.28 (d, 1H), 4.06 (d, 1H), 4.03 (d, 1H), 3.82(d, 2H); MS (EI) for C₂₄H₁₇F₃IN₅O₂: 544 (MH⁺).

Example 3(kkk)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{2-[(2,2,3,3,3-pentafluoropropyl)amino]ethyl}azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.58 (br s, 1H), 7.56 (dd, 1H), 7.37 (dd,1H), 7.34-7.28 (m, 1H), 7.22-7.13 (m, 1H), 6.68 (ddd, 1H), 5.82 (br s,1H), 4.06 (d, 1H), 3.91 (t, 210), 3.70 (d, 1H), 3.40-3.25 (m, 2H), 2.76(d, 2H), 2.40-2.31 (m, 1H); MS (EI) for C₂₀H₁₆F₈IN₃O₂: 610 (MH⁺).

Example 3(mmm)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{2-[(3,3,3-trifluoropropyl)amino]ethyl}azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.58 (br s, 1H), 7.57 (dd, 1H), 7.37 (dd,1H), 7.34-7.28 (m, 1H), 7.22-7.13 (m, 1H), 6.68 (ddd, 1H), 5.76 (br s,1H), 4.05 (d, 1H), 3.88 (d, 2H), 3.70 (d, 1H), 2.71 (t, 2H), 2.63 (s,2H), 2.41-2.26 (m, 2H); MS (EI) for C₂₀H₁₈F₆IN₃O₂: 574 (MH⁺).

Example 3(nnn)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2,3-dihydro-1H-inden-1-ylamino)methyl]azetidin-3-olacetate salt: ¹H NMR (400 MHz, DMSO): 8.61-8.56 (m, 1H), 7.55 (d, 1H),7.37-7.07 (m, 8H), 6.71-6.64 (m, 1H), 4.16-4.05 (m, 2H), 3.98-3.85 (m,2H), 3.72-3.68 (m, 1H), 2.90-2.82 (m, 1H), 2.74-2.64 (m, 2H), 1.91 (s,3H), 1.73-1.63 (m, 1H); MS (EI) for C₂₆H₂₃F₃IN₃O₂: 594 (MH⁺).

Example 3(ooo)

3-[(cyclooctylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, DMSO): 8.56 (s, 1H), 7.55 (d, 1H),7.20-7.14 (m, 2H), 6.70-6.66 (m, 1H), 4.03-3.98 (m, 1H), 3.92-3.86 (m,2H), 3.72-3.67 (m, 1H), 2.60 (s, 2H), 1.90 (s, 3H), 1.64-1.22 (m, 15H);MS (EI) for C₂₅H₂₉F₃IN₃O₂: 588 (MH⁺).

Example 3(ppp)

3-[(cycloheptylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, DMSO): 8.55 (s, 1H), 7.55 (d, 1H),7.36-7.28 (m, 2H), 7.21-7.14 (m, 1H), 6.70-6.66 (m, 1H), 4.04-4.00 (m,1H), 3.92-3.85 (m, 2H), 3.71-3.66 (m, 1H), 2.60 (s, 2H), 1.90 (s, 3H),1.70-1.13 (m, 13H); MS (EI) for C₂₄H₂₇F₃IN₃O₂: 574 (MH⁺).

Example 3(qqq)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-pyridin-3-ylethyl)amino]methyl}azetidin-3-olacetate salt: ¹H NMR (400 MHz, DMSO): 8.58 (s, 1H), 8.42-8.37 (m, 2H),7.62-7.54 (m, 2H), 7.38-7.27 (m, 3H), 7.21-7.14 (m, 1H), 6.71-6.66 (m,1H), 4.06-4.02 (m, 1H), 3.90-3.86 (m, 2H), 3.72-3.68 (m, 1H), 2.80-2.64(m, 6H), 1.90 (s, 3H); MS (EI) for C₂₄H₂₂F₃IN₄O₂: 583 (MH⁺).

Example 3(rrr)

N-cyclohexyl-N2-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}-2-methylalaninamideacetate salt: ¹H NMR (400 MHz, DMSO): 8.66 (br s 1H), 8.55 (s, 1H),7.93-7.90 (m, 1H), 7.58 (d, 1H), 7.40-7.31 (m, 2H), 7.24-7.17 (m, 1H),6.71-6.66 (m, 1H), 6.60 (br s, 1H), 4.28-4.23 (m, 1H), 4.14-4.02 (m,2H), 3.89-3.83 (m, 1H), 3.12 (br s, 2H), 1.90 (s, 3H), 1.74-1.42 (m,11H), 1.31-1.02 (m, 6H); MS (EI) for C₂₇H₃₂F₃IN₄O₃: 645 (MH⁺).

Example 3(ss)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl}azetidin-3-olacetate salt: ¹H NMR (400 MHz, DMSO): 8.56 (s, 1H), 7.56 (d, 1H),7.38-7.27 (m, 2H), 7.20-7.14 (m, 1H), 6.71-6.66 (m, 1H), 4.05-4.01 (m,1H), 3.91-3.78 (m, 4H), 3.71-3.67 (m, 1H), 3.25-3.18 (m, 2H), 2.60 (s,2H), 2.36 (d, 2H), 1.90 (s, 3H), 1.57-1.50 (m, 3H), 1.13-1.02 (m, 2H);MS (EI) for C₂₃H₂₅F₃IN₃O₃: 576 (MH⁺).

Example 3(ttt)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(dimethylamino)-1-methylethyl]amino}methyl)azetidin-3-oltrifluoroacetate salt: ¹H NMR (400 MHz, DMSO): 8.59-8.54 (m, 1H), 7.56(d, 1H), 7.38-7.28 (m, 2H), 7.21-7.13 (m, 1H), 6.71-6.63 (m, 1H),4.04-3.95 (m, 1H), 3.88-3.78 (m, 2H), 3.73-3.68 (m, 1H), 2.70-2.50 (m,3H), 2.08 (s, 6H), 1.88 (s, 2H), 0.85-0.82 (m, 3H); MS (EI) forC₂₂H₂₆F₃IN₄O₂: 563 (MH⁺).

Example 3(uuu)

N-cyclopropyl-1-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)cyclopentanecarboxamidetrifluoroacetate salt: ¹H NMR (400 MHz, DMSO): 8.80 (br s, 1H), 8.58 (s,1H), 8.04 (s, 1H), 7.59 (d, 1H), 7.40-7.31 (m, 2H), 7.25-7.16 (m, 1H),6.74-6.58 (m, 2H), 4.26-3.82 (m, 4H), 3.10 (br s, 2H), 2.69-2.64 (m,1H), 2.11-1.88 (m, 4H), 1.82-1.61 (m, 4H), 0.67-0.62 (m, 2H), 0.52-0.48(m, 2H); MS (EI) for C₂₆H₂₉F₃IN₄O₃: 629 (MH⁺).

Example 3(vvv)

N2-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}-N-ethyl-2-methylalaninamideacetate salt: ¹H NMR (400 MHz, DMSO): 8.60 (s, 1H), 7.60-7.72 (m, 1H),7.56 (d, 1H), 7.38-7.30 (m, 2H), 7.22-7.14 (m, 1H), 6.69-6.63 (m, 1H),4.07-4.04 (m, 1H), 3.95-3.90 (m, 2H), 3.72-3.68 (m, 1H), 3.05-3.01 (m,2H), 2.47 (br s, 2H), 1.90 (s, 3H), 1.09 (s, 6H), 0.94 (t, 3H); MS (EI)for C₂₃H₂₆F₃IN₄O₃: 591 (MH⁺).

Example 3(www)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2-methylhydrazino)methyl]azetidin-3-olacetate salt: ¹H NMR (400 MHz, DMSO): 8.54 (s, 1H), 7.57 (d, 1H),7.38-7.30 (m, 2H), 7.19-7.12 (m, 1H), 6.69-6.63 (m, 1H), 4.04-4.01 (m,1H), 3.92-3.84 (m, 2H), 3.68-3.63 (m, 1H), 2.55 (s, 2H), 2.39 (s, 3H),1.90 (s, 3H); MS (EI) for C₁₈H₁₈F₃IN₄O₂: 507 (MH⁺).

Example 3(xxx)

3-[(azetidin-3-ylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, DMSO): 7.57 (d, 1H), 7.39-7.30 (m, 2H),7.20-7.13 (m, 1H), 6.70-6.65 (m, 1H), 4.10-4.04 (m, 1H), 3.90-3.83 (m,2H), 3.78-3.67 (m, 3H), 3.61-3.53 (m, 1H), 3.48-3.42 (m, 2H), 2.61-2.54(m, 2H), 1.90 (s, 3H); MS (EI) for C₂₀H₂₀F₃IN₄O₂: 533 (MH⁺).

Example 3(yyy)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1,3-thiazol-2-ylamino)methyl]azetidin-3-olacetate salt: ¹H NMR (400 MHz, DMSO): 8.60 (s, 1H), 7.57 (d, 1H),7.38-7.28 (m, 2H), 7.20-7.13 (m, 1H), 6.75 (d, 1H), 6.70-6.64 (m, 1H),5.93 (d, 1H), 4.26-4.22 (m, 1H), 4.11-4.08 (m, 1H), 4.00-3.88 (m, 3H),3.74-3.70 (m, 1H), 1.90 (s, 3H); MS (EI) for C₂₀H₁₆F₃IN₄O₂S: 561 (MH⁺).

Example 3(zzz)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[3-(methyloxy)phenyl]amino}methyl)azetidin-3-ol:¹H NMR (400 MHz, DMSO): 8.57 (s, 1H), 7.56 (d, 1H), 7.38-7.30 (m, 2H),7.20-7.12 (m, 1H), 6.95-6.91 (m, 1H), 6.70-6.66 (m, 1H), 6.21-6.17 (m,2H), 6.14-6.10 (m, 1H), 5.94 (s, 1H), 5.49-5.44 (m, 1H), 4.14-4.10 (m,1H), 3.98-3.93 (m, 2H), 3.78-3.75 (m, 1H), 3.65 (s, 3H), 3.21 (d, 2H);MS (EI) for C₂₄H₂₁F₃IN₃O₃: 584 (MH⁺).

Example 3(ab)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[4-(methyloxy)phenyl]amino}methyl)azetidin-3-ol:¹H NMR (400 MHz, DMSO): 8.56 (s, 1H), 7.58 (d, 1H), 7.39-7.30 (d, 2H),7.20-7.13 (m, 1H), 6.71-6.66 (m, 3H), 6.55 (d, 2H), 5.93 (s, 1H),5.00-4.95 (m, 1H), 4.14-4.08 (m, 1H), 3.98-3.92 (m, 2H), 3.79-3.74 (m,1H), 3.63 (s, 3H), 3.13 (d, 2H); MS (EI) for C₂₄H₂₁F₃IN₃O₃: 584 (MH⁺).

Example 3(ac)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(ethyloxy)ethyl]amino}methyl)azetidin-3-ol:¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d, 1H), 7.31-7.26(m, 1H), 7.08-7.00 (q, 1H), 6.65-6.58 (t, 1H), 4.24-4.16 (d, 1H),4.08-3.98 (t, 2H), 3.92-3.85 (d. 1H), 3.60-3.55 (t, 2H), 3.54-3.47 (q,2H), 3.01-2.96 (s, 2H), 2.94-2.89 (t, 2H), 1.20-1.15 (t, 3H); MS (EI)for C₂₁H₂₃F₃IN₃O₃: 550 (MH⁺).

Example 3(ad)

3-({[2,2-bis(methyloxy)ethyl]amino}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.32 (d,1H), 7.30-7.24 (m, 1H), 7.08-7.00 (q, 1H), 6.65-6.57 (t, 1H), 4.48-4.42(t, 1H), 4.20-4.11 (d, 1H), 4.02-3.93 (t, 2H), 3.86-3.80 (d, 1H),3.38-3.34 (s, 6H), 2.84-2.80 (s, 2H), 2.75-2.70 (d, 2H), 1.93-1.87 (s,3H); MS (EI) for C₂₁H₂₃F₃IN₃O₄: 566 (MH⁺).

Example 3(ae)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3-hydroxypropy))amino]methyl}azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.38-7.33 (d,1H), 7.32-7.26 (m, 1H), 7.09-7.00 (q, 1H), 6.66-6.58 (t, 1H), 4.31-4.23(d, 1H), 4.16-4.05 (t, 2H), 3.99-3.89 (d, 1H), 3.70-3.64 (t, 2H),3.26-3.22 (s, 2H), 3.11-3.04 (t, 2H), 1.93-1.89 (s, 3H), 1.89-1.82 (t,3H); MS (EI) for C₂₀H₂₁F₃IN₃O₃: 536 (MH⁺).

Example 3(af)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-pyridin-4-ylethyl)amino]methyl}azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 8.36-8.32 (d, 2H), 7.38-7.33 (d,1H), 7.26-7.14 (m, 3H), 7.00-6.91 (q, 1H), 4.12-4.04 (d, 1H), 3.96-3.88(t, 2H), 3.80-3.73 (d, 2H), 2.92-2.74 (m, 6H), 1.87-1.84 (s, 3H); MS(EI) for C₂₄H₂₂F₃IN₄O₂: 583 (MH⁺).

Example 3(ag)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[1-(phenylmethyl)pyrrolidin-3-yl]amino}methyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.47-7.24 (m, 8H), 7.08-7.00 (q,1H), 6.64-6.57 (t, 1H), 4.19-4.11 (d, 1H), 4.05-3.81 (m, 5H), 3.52-3.44(m, 1H), 3.09-2.99 (m, 2H), 2.91-2.76 (m, 3H), 1.93-1.91 (s, 3H),1.82-1.71 (m, 1H); MS (EI) for C₂₈H₂₈F₃IN₄O₂: 637 (MH⁺).

Example 3(ah)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(2-thienyl)ethyl]amino}methyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.47-7.42 (d, 1H), 7.36-7.31 (d,1H), 7.30-7.24 (m, 1H), 7.21-7.17 (d, 1H), 7.08-7.00 (q, 1H), 6.93-6.89(t, 1H), 6.86-6.83 (d, 1H), 6.64-6.57 (t, 1H), 4.18-4.11 (d, 1H),4.01-3.93 (t, 2H), 3.85-3.78 (d, 1H), 3.04-2.97 (t, 2H), 2.92-2.87 (t,2H), 2.82-2.78 (s, 2H), 1.92-1.87 (s, 3H); MS (EI) for C₂₃H₂₁F₃IN₃O₂S:588 (MH⁺).

Example 3(ai)

3-[({2-[bis(1-methylethyl)amino]ethyl}amino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d,1H), 7.31-7.26 (m, 1H), 7.08-7.00 (q, 1H), 6.65-6.58 (t, 1H), 4.18-4.13(d, 1H), 4.06-3.98 (t, 2H), 3.88-3.82 (d, 2H), 3.57-3.47 (q, 2H),3.05-2.99 (t, 2H), 2.92-2.85 (t, 4H), 1.92-1.88 (s, 3H), 1.28-1.22 (d,121); MS (EI) for C₂H₃₂F₃IN₄O₂: 605 (MH⁺).

Example 3(aj)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(phenyloxy)ethyl]amino}methyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.36-7.31 (d, 1H), 7.26-7.22 (d,1H), 7.20-7.13 (m, 3H), 6.97-6.89 (t, 1H), 6.86-6.80 (m, 3H), 6.54-6.47(t, 1H), 4.13-4.07 (d, 1H), 4.01-3.96 (t, 2H), 3.79-3.74 (d, 1H),2.97-2.91 (t, 2H), 2.84-2.79 (s, 2H), 1.84-1.81 (s, 3H); MS (EI) forC₂₅H₂₃F₃IN₃O₃: 598 (MH⁺).

Example 3(ak)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxypropyl)amino]methyl}azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d,1H), 7.31-7.26 (m, 1H), 7.08-7.00 (q, 1H), 6.65-6.58 (t, 1H), 4.27-4.19(d, 1H), 4.10-4.00 (m, 2H), 3.15-3.00 (t, 2H), 3.57-3.47 (q, 2H),3.15-3.00 (t, 2H), 2.87-2.81 (d, 1H), 2.72-2.64 (t, 1H), 1.94-1.91 (s,3H), 1.19-1.15 (d, 3H); MS (EI) for C₂₀H₂₁F₃IN₃O₃: 536 (MH⁺).

Example 3(am)

1-({³,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[({2-[(1-methylethyl)oxy]ethyl}amino)methyl]azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d,1H), 7.31-7.26 (m, 1H), 7.08-7.00 (q, 1H), 6.65-6.58 (t, 1H), 4.21-4.13(d, 1H), 4.04-3.95 (t, 2H), 3.88-3.82 (d, 1H), 3.64-3.51 (m, 3H),2.89-2.84 (s, 2H), 2.83-2.77 (t, 2H), 1.91-1.89 (s, 3H), 1.15-1.12 (d,6H); MS (EI) for C₂₂H₂₅F₃IN₃O₃: 564 (MH⁺).

Example 3(an)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-ethylpiperidin-3-yl)amino]methyl}azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d,1H), 7.31-7.26 (m, 1H), 7.08-7.00 (q, 1H), 6.65-6.58 (t, 1H), 4.174.10(d, 1H), 4.04-3.95 (t, 2H), 3.88-3.82 (d, 1H), 3.24-3.06 (m, 2H),2.95-2.75 (m, 6H), 2.76-2.46 (m, 2H), 1.93-1.90 (s, 3H), 1.74-1.62 (m,1H), 1.44-1.31 (m, 1H), 1.28-1.20 (t, 3H); MS (EI) for C₂₄H₂₈F₃IN₄O₂:589 (MH⁺).

Example 3(ao)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]amino}methyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d,1H), 7.31-7.26 (m, 1H), 7.08-7.00 (q, 1H), 6.65-6.58 (t, 1H), 4.20-4.13(d, 1H), 4.00-3.90 (t, 2H), 3.83-3.75 (d, 1H), 2.84-2.78 (s, 2H),2.53-2.48 (s, 2H), 1.93-1.87 (s, 3H); MS (EI) for C₂₁H₁₉F₃IN₅O₃: 574(MH⁺).

Example 3(ap)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-methylbutyl)amino]methyl}azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.38-7.33 (d,1H), 7.32-7.27 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (t, 1H), 4.25-4.19(d, 1H), 4.12-4.02 (t, 2H), 3.96-3.90 (d, 1H), 3.16-2.96 (m, 3H),1.91-1.89 (s, 3H), 1.68-1.57 (m, 1H), 1.49-1.29 (m, 3H), 1.23-1.18 (d,3H), 0.99-0.92 (t, 3H); MS (EI) for C₂₂H₂₅F₃N₃O₂: 548 (MH⁺).

Example 3(aq)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-methylpropyl)amino]methyl}azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d,1H), 7.32-7.26 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (t, 1H), 4.27-4.20(d, 1H), 4.14-4.03 (t, 2H), 3.98-3.92 (d, 1H), 3.20-3.16 (s, 2H),3.07-2.97 (m, 1H), 1.91-1.89 (s, 3H), 1.80-1.70 (m, 1H), 1.54-1.41 (m,1H), 1.26-1.22 (d, 3H), 1.00-0.94 (t, 3H); MS (EI) for C₂₁H₂₃F₃IN₃O₂:534 (MH⁺).

Example 3(ar)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-methylbutyl)amino]methyl}azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d,1H), 7.32-7.26 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (t, 1H), 4.26-4.19(d, 1H), 4.10-4.01 (t, 2H), 3.94-3.87 (d, 1H), 3.05-2.99 (s, 2H),2.77-2.70 (m, 1H), 2.61-2.54 (m, 1H), 1.91-1.89 (s, 3H), 1.73-1.61 (m,1H), 1.49-1.39 (m, 1H), 1.24-1.12 (m, 1H), 0.94-0.84 (m, 6H); MS (EI)for C₂₂H₂₅F₃IN₃O2: 548 (MH⁺).

Example 3(as)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(pentylamino)methyl]azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d,1H), 7.32-7.26 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (1, 1H), 4.29-4.23(d, 1H), 4.15-4.05 (t, 2H), 3.98-3.90 (d, 1H), 3.21-3.18 (s, 2H),2.93-2.86 (m, 2H), 1.91-1.89 (s, 3H), 1.70-1.60 (m, 2H), 1.42-1.29 (m,4H), 0.97-0.90 (t, 3H); MS (EI) for C₂₂H₂₅F₃IN₃O₂: 548 (MH⁺).

Example 3(at)

3-[(cyclohexylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.38-7.34 (d,1H), 7.33-7.27 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (t, 1H), 4.25-4.19(d, 1H), 4.14-4.03 (t, 2H), 3.98-3.90 (d, 1H), 3.21-3.18 (s, 2H),2.93-2.86 (m, 1H), 2.07-2.00 (d, 2H), 1.92-1.90 (s, 3H), 1.89-1.82 (d,2H), 1.73-1.66 (d, 1H), 1.42-1.14 (m, 5H); MS (EI) for C₂₃H₂₅F₃IN₃O₂:560 (MH⁺).

Example 3(au)

3-[(azepan-3-ylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d,1H), 7.32-7.26 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (t, 1H), 4.19-4.13(d, 1H), 4.05-3.95 (t, 2H), 3.90-3.81 (d, 1H), 3.37-3.34 (s, 2H),3.22-3.03 (m, 2H), 2.91-2.64 (m, 3H), 1.93-1.89 (s, 3H), 1.88-1.52 (m,6H); MS (EI) for C₂₃H₂₆F₃IN₄O₂: 575 (MH⁺).

Example 3(av)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(2,3-dihydro-1H-indol-3-yl)ethyl]amino}methyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.58-7.54 (d, 1H), 7.48-7.43 (d,1H), 7.36-7.33 (d, 1H), 7.31-7.26 (m, 1H), 7.14-6.99 (m, 4H), 6.65-6.58(t, 1H), 4.25-4.19 (d, 1H), 4.10-4.02 (t, 2H), 3.95-3.88 (d, 1H),3.23-3.03 (m, 9H), 1.94-1.92 (s, 3H); MS (EI) for C₂₇H₂₆F₃IN₄O₂: 623(MH⁺).

Example 3(aw)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1,3,5-triazin-2-ylamino)methyl]azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 8.48-8.46 (s, 1H), 8.36-8.34 (s,1H), 7.48-7.43 (d, 1H), 7.37-7.33 (d, 1H), 7.28-7.22 (m, 1H), 7.06-6.98(q, 1H), 6.65-6.58 (t, 1H), 4.24-4.18 (d, 1H), 4.10-3.96 (t, 2H),3.84-3.78 (d, 1H), 3.69-3.67 (s, 2H), 1.99-1.97 (s, 3H); MS (EI) forC₂₀H₁₆F₃IN₆O₂: 557 (MH⁺).

Example 3(ax)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(4-hydroxycyclohexyl)amino]methyl}azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d,1H), 7.32-7.26 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (t, 1H), 4.22-4.15(d, 1H), 4.08-3.99 (t, 2H), 3.93-3.87 (d, 1H), 3.56-3.47 (m, 1H),3.05-3.02 (s, 2H), 2.76-2.68 (m, 1H), 2.03-1.96 (m, 41H), 1.93-1.89 (s,3H), 1.35-1.23 (m, 4H); MS (EI) for C₂₃H₂₅F₃IN₃O₃: 576 (MH⁺).

Example 3(ay)

3-[(cyclopent-3-en-1-ylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d,1H), 7.32-7.26 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (t, 1H), 5.70-5.65(s, 2H), 4.20-4.14 (d, 1H), 4.03-3.95 (t, 2H), 3.90-3.81 (d, 1H),3.58-3.50 (m, 1H), 2.90-2.86 (s, 2H), 2.68-2.58 (m, 2H), 2.26-2.16 (m,2H), 1.93-1.89 (s, 3H); MS (EI) for C₂₂H₂₁F₃IN₃O₂: 544 (MH⁺).

Example 3(az)

N-[4-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)phenyl]acetamideacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d,1H), 7.27-7.20 (m, 3H), 7.09-7.01 (q, 1H), 6.65-6.55 (m, 3H), 4.22-4.16(d, 1H), 4.08-3.98 (t, 2H), 3.88-3.82 (d, 111H), 3.28-3.24 (s, 2H),2.08-2.05 (s, 3H), 2.91-2.64 (m, 3H), 1.93-1.89 (s, 3H); MS (EI) forC₂₅H₂₂F₃IN₄O₃: 611 (MH⁺).

Example 3(ba)

N-[3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)phenyl]acetamideacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.36-7.33 (d,1H), 7.27-7.20 (m, 1H), 7.04-6.96 (m, 3H), 6.72-6.68 (d, 1H), 6.65-6.58(t, 1H), 6.40-6.35 (d, 1H), 4.24-4.18 (d, 1H), 4.08-3.98 (t, 2H),3.87-3.81 (d, 1H), 3.28-3.25 (s, 2H), 2.10-2.07 (s, 3H), 1.97-1.95 (s,3H); MS (EI) for C₂₅H₂₂F₃IN₄O₃: 611 (MH⁺).

Example 3(bc)

(1R,2S)-4-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)cyclopentane-1,2-diolacetate salt: ¹H NMR (400 MHz, DMSO): 8.58-8.54 (s, 1H), 7.61-7.53 (d,1H), 7.39-7.28 (m, 2H), 7.21-7.13 (m, 1H), 6.71-6.63 (t, 1H), 5.58-5.64(s, 1H), 5.63-5.58 (s, 1H), 4.06-4.01 (d, 1H), 3.90-3.84 (t, 2H),3.72-3.66 (d, 1H), 3.31-3.26 (m, 3H), 2.61-2.57 (s, 2H), 2.46-2.36 (m,2H), 2.02-1.93 (dd, 2H), 1.91-1.88 (s, 3H); MS (EI) for C₂₂H₂₃F₃IN₃O₄:578 (MH⁺).

Example 3(bd)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[1-(hydroxymethyl)cyclohexyl]amino}methyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d,1H), 7.32-7.26 (m, 1H), 7.09-7.01 (q, 1H), 6.65-6.58 (t, 1H), 4.22-4.15(d, 1H), 4.08-3.99 (t, 2H), 3.89-3.83 (d, 1H), 3.49-3.45 (s, 2H),2.86-2.80 (s, 2H), 1.91-1.89 (s, 3H), 1.67-1.34 (m, 10H); MS (EI) forC₂₄H₂₇F₃IN₃O: 590 (MH⁺).

Example 3(be)

3-{[(3-chlorophenyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.37-7.33 (d,1H), 7.32-7.26 (m, 1H), 7.08-6.98 (m, 2H), 6.65-6.55 (m, 3H), 6.53-6.44(d, 1H), 4.22-4.15 (d, 1H), 4.06-3.98 (t, 2H), 3.88-3.82 (d, 1H),3.27-3.24 (s, 2H), 1.91-1.89 (s, 3H); MS (EI) for C₂₃H₁₈ClF₃N₃O₂: 588(MH⁺).

Example 3(bf)

3-{[(4-chlorophenyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.45-7.40 (d, 1H), 7.35-7.30 (d,1H), 7.28-7.22 (m, 1H), 7.06-6.97 (m, 3H), 6.62-6.54 (m, 3H), 6.53-6.44(d, 1H), 422-4.15 (d, 1H), 4.06-3.98 (t, 2H), 3.88-3.82 (d, 1H),3.26-3.22 (s, 2H), 1.96-1.94 (s, 3H); MS (EI) for C₂₃H₁₈ClF₃IN₃O₂: 588(MH⁺).

Example 3(bg)

3-[(5-amino-3-methyl-1H-pyrazol-1-yl)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.38-7.33 (d, 1H), 7.28-7.24 (d,1H), 7.21-7.15 (m, 1H), 6.98-6.90 (q, 1H), 6.56-6.49 (t, 1H), 5.16-5.14(s, 1H), 4.36-4.30 (d, 1H), 4.22-4.16 (d, 1H), 3.99-3.97 (s, 1H),3.95-3.90 (d, 1H), 3.77-3.71 (d, 1H), 1.96-1.92 (s, 3H), 1.85-1.82 (s,3H); MS (EI) for C₂₁H₁₉F₃IN₅O₂: 558 (MH⁺).

Example 3(bh)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(5-methyl-1H-pyrazol-3-yl)amino]methyl}azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.38-7.33 (d, 1H), 7.28-7.24 (d,1H), 7.21-7.15 (m, 1H), 6.98-6.90 (q, 1H), 6.56-6.49 (t, 1H), 5.22-5.19(s, 1H), 4.15-4.08 (d, 1H), 4.02-3.88 (m, 2H), 3.75-3.68 (d, 1H),3.20-3.18 (s, 2H), 2.07-2.05 (s, 3H), 1.85-1.82 (s, 3H); MS (EI) forC₂₁H₁₉F₃IN₅O₂: 558 (MH⁺).

Example 3(bi)

3-[(diethylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.54 (s, 1H), 7.58-7.55 (dd, 1H), 7.38-7.35(dt, 1H), 7.33-7.31 (m, 1H), 7.22-7.15 (m, 1H), 6.69-6.64 (m, 1H), 5.56(b, 1H), 4.06-4.04 (d, 1H), 3.90-3.88 (m, 2H), 3.72-3.69 (d 1H),2.51-2.49 (m, 6H), 0.86-0.83 (t, 6H); MS (EI) for C₂₁H₂₃F₃IN₃O₂: 534(MH⁺).

Example 3(bj)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(dimethylamino)methyl]azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.56 (s, 1H), 7.59-7.56 (dd, 1H), 7.38-7.36(dt, 1H), 7.34-7.33 (m, 1H), 7.21-7.14 (m, 1H), 6.71-6.65 (m, 1H), 5.55(b, 1H), 4.07-4.05 (d, 1H), 3.89-3.84 (t, 2H), 3.74-3.719 (d, 1H), 2.46(m, 2H), 2.19 (br s, 6H); MS (EI) for C₁₉H₁₉F₃IN₃O₂: 506 (MH⁺).

Example 3(bk)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxy-1,1-dimethylethyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.40 (s, 1H), 7.38 (dd, 1H), 7.33-7.30 (m, 1H),7.12 (m, 1H), 6.85-6.79 (m, 1H), 6.63-6.57 (m, 1H), 4.22-4.11 (br m,4H), 3.55 (s, 2H), 3.15 (s, 2H), 1.32 (s, 6-1); MS (EI) forC₂₁H₂₃F₃IN₃O₃: 550 (MH⁺).

Example 3(bm)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(prop-2-en-1-ylamino)methyl]azetidin-3-ol):¹H NMR (400 MHz, CDCl₃): 8.47 (s, 1H), 7.40 (dd, 1H), 7.34-7.31 (m, 1H),7.12 (m, 1H), 6.83-6.77 (m, 1H), 6.64-6.59 (m, 1H), 6.64-6.59 (m, 1H),5.88-5.78 (m, 1H), 5.00-5.12 (m, 2H), 4.13 (br m, 4H), 3.26 (d, 2H),2.88 (d, 2H), 2.02 (s, 1H); MS (EI) for C₂₁H₁₉F₃IN₃O₂: 518 (MH⁺).

Example 3(bn)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(tetrahydro-2H-pyran-4-yl)ethyl]amino}methyl)azetidin-3-ol):¹H NMR (400 MHz, CDCl₃): 8.45 (s, 1H), 7.39 (dd, 1H), 7.34-7.31 (m, 1H),7.14-7.10 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.58 (m, 1H), 4.26-4.04 (m,4H), 3.95 (dd, 2H), 3.35 (t, 2H), 2.92 (d, 2H), 2.67 (m, 2H), 1.40-1.25(m, 8H); MS (EI) for C₂₄H₂₇F₃IN₃O₃: 590 (MH⁺).

Example 3(bo)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1,1-dimethylprop-2-yn-1-yl)amino]methyl}azetidin-3-ol):¹H NMR (400 MHz, CDCl₃): 8.46 (s, 1H), 7.39 (dd, 1H), 7.33-7.30 (m, 1H),7.15-7.11 (m, 1H), 6.84-6.77 (m, 1H), 6.64-6.58 (m, 1H), 4.20 (br, 1H),4.07 (br, 1H), 2.92 (s, 2H), 1.58 (m, 4H), 0.92 (dd, 6 h); MS (EI) forC₂₂H₂₁F₃IN₃O₂: 572 (MH⁺).

Example 3(bp)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)azetidin-3-ol):¹H NMR (400 MHz, CDCl₃): 8.44 (s, 1H), 7.33-7.14 (m, 3H), 7.00 (m, 1H),6.67 (dd, 1H), 6.59 (s, 1H), 6.44 (m, 1H), 3.93 (d, 2H), 2.75 (m, 2H),2.60 (m, 1H), 2.42 (m, 1H) 2.02 (AcOH; s, 3H), 1.86 (m, 4H); MS (EI) forC₂₂H₂₁F₃IN₅O₂: 572 (MH⁺).

Example 3(bq)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[3-(ethyloxy)propyl]amino}methyl)azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.49 (s, 1H), 7.39 (dd, 1H), 7.34-7.31 (m, 1H),7.14-7.10 (m, 1H), 6.83-6.76 (m, 1H), 6.64-6.58 (m, 1H), 4.26-4.03 (brm, 4H), 3.53-3.44 (m, 4H), 2.92-2.73 (m, 4H), 1.72 (m, 2H) 1.18 (t, 3H);MS (EI) for C₂₂H₂₃F₃IN₃O₃: 564 (MH⁺).

Example 3(br)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3,3-dimethylbutyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.46 (s, 1H), 7.39 (dd, 1H), 7.34-7.31 (m, 1H),7.14-7.10 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.58 (m, 1H), 4.18 (br, 3H),3.15 (s, 2H), 2.71 (m, 2H) 2.05 (AcOH; s, 3H), 1.43 (m, 2H), 0.90 (s,9H); MS (EI) for C₂₃H₂₇F₃IN₃O₂: 562 (MH⁺).

Example 3(bs)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3-methylbutyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.46 (s, 1H), 7.39 (dd, 1H), 7.34-7.30 (m, 1H),7.14-7.11 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.59 (m, 1H), 4.27-3.61 (brm, 6H), 2.98 (m, 2H), 2.72 (t, 2H) 2.05 (AcOH; s, 3H), 1.61 (m, 1H),1.43 (m, 2H), 0.90 (d, 6H); MS (EI) for C₂₂H₂F₃IN₃O₂: 547 (MH⁺).

Example 3(bt)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[3-(dimethylamino)propyl]amino}methyl)azetidin-3-ol:MS (EI) for C₂₂H₂₆F₃IN₄O₂: 563 (MH⁺).

Example 3(bu)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[3-(1H-imidazol-1-yl)propyl]amino}methyl)azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.46 (s, 1H), 7.53 (s, 1H), 7.40 (dd, 1H),7.34-7.30 (m, 1H), 7.14-7.09 (m, 1H), 7.05 (s, 1H), 6.89 (s, 1H),6.84-6.77 (m, 1H), 6.63-6.59 (m, 1H), 4.24-4.00 (br m, 6H), 2.84 (m,2H), 2.61 (m, 2H), 1.94 (m, 2H); MS (EI) for C₂₃H₂₁F₃IN₃O₂: 586 (MH⁺).

Example 3(bv)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(methylthio)ethyl]amino}methyl)azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.49 (s, 1H), 7.39 (dd, 1H), 7.34-7.31 (m, 1H),7.14-7.11 (m, 1H), 6.83-6.77 (m, 1H), 6.63-6.59 (m, 1H), 4.26-4.03 (brm, 4H), 2.88 (s, 2H), 2.82 (t, 2H), 2.62 (t, 2H), 2.08 (s, 3H); MS (EI)for C₂₃H₂₁F₃INO₂S: 552 (MH⁺).

Example 3(bw)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1,1,3,3-tetramethylbutyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.49 (s, 1H), 7.38 (dd, 1H), 7.34-7.30 (m, 1H),7.14-7.11 (m, 1H),6.83-6.77 (m, 1H), 6.64-6.59 (m, 1H), 4.25-4.01 (br m,4H), 2.82 (s, 2H), 1.45 (s, 2H), 1.15 (s, 6H), 0.90 (s, 9H); MS (EI) forC₂₅H₃₁F₃IN₃O₂: 590 (MH⁺).

Example 3(bx)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1,1-dimethylpropyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.50 (s, 1H), 7.39 (dd, 1H), 7.35-7.30 (m, 1H),7.15-7.11 (m, 1H), 6.83-6.77 (m, 1H), 6.65-6.59 (m, 1H), 4.27-4.01 (brm, 4H), 2.82 (s, 2H), 1.46 (s, 2H), 1.08 (s, 6H), 0.89 (s, 3H); MS (EI)for C₂₂H₂₁F₃IN₄O₃: 548 (MH⁺).

Example 3(by)

3-{[(3-amino-2-hydroxypropyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:MS (EI) for C₂₃H₂₂F₃IN₄O₃: 551 (MH⁺).

Example 3(bz)

1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}pyrrolidin-3-ol:MS (EI) for C₂₁H₂₁F₃IN₃O₃: 548 (MH⁺).

Example 3(ca)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({(2S)-2-[(methyloxy)methyl]pyrrolidin-1-yl}methyl)azetidin-3-ol:MS (EI) for C₂₃H₂₅F₃IN₃O₃: 576 (MH⁺).

Example 3(cb)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxyphenyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.46 (s, 1H), 7.41 (dd, 1H), 7.35-7.30 (m, 1H),7.15-7.11 (m, 1H), 6.89-5.98 (m, 6H), 4.92 (s, 1H), 4.28-4.05 (br m,4H), 3.44 (s, 2H); MS (EI) for C₂₃H₁₉F₃IN₃O₃: 570 (MH⁺).

Example 3(cd)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(4-hydroxyphenyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz. CDCl₃): 8.46 (s, 1H), 7.78 (s, 1H), 7.40-7.05 (m, 4H),6.72 (m, 1H), 6.62 (d, 1H), 6.50 (m, 1H), 6.42 (d, 1H) 4.04-3.98 (m,4H), 3.18 (s, 2H); MS (EI) for C₂₃H₁₉F₃IN₃O₃: 570 (MH⁺).

Example 3(ce)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3-hydroxyphenyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.52 (s, 1H), 8.22 (s, 1H), 7.39 (dd, 1H),7.34-7.31 (m, 1H), 7.14-7.11 (m, 1H), 6.85 (dd, 1H), 6.84-6.77 (m, 1H),6.63-6.59 (m, 1H), 6.15 (d, 1H) 6.09-6.01 (m, 3H), 4.16-3.95 (br m, 4H),3.22 (d, 2H) 2.15 (AcOH; s, 3H); MS (EI) for C₂₃H₁₉F₃IN₃O₃: 570 (MH⁺).

Example 3(ef)

1-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(phenyloxy)methyl]azetidin-3-ol:MS (EI) for C₂₃H₁₈F₃IN₂O₃: 555 (MH⁺).

Example 3(cg)

3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)propane-1,2-diol:MS (EI) for C₂₀H₂₁F₃IN₃O₄: 552 (MH⁺).

Example 3(ch)

1-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(phenylthio)methyl]azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.46 (s, 1H), 7.45-7.23 (m, 5H), 7.14-7.05 (m,1H), 6.78 (dd, 1H), 6.60 (m, 1H), 4.14-3.92 (br in, 4H), 3.33 (s, 2H);MS (EI) for C₂₃H₁₈F₃IN₂O₂: 571 (MH⁺).

Example 3(ci)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(4-hydroxybutyl)amino]methyl}azetidin-3-ol):¹H NMR (400 MHz, CDCl₃): 8.43 (s, 1H), 7.38 (dd, 1H), 7.34-7.30 (m, 1H),7.14-7.10 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.58 (m, 1H), 4.26-4.04 (m,4H), 3.61 (m, 2H), 2.96 (s, 2H), 2.73 (s, 2H); MS (EI) forC₂₁H₂₃F₃IN₃O₃: 550 (MH⁺).

Example 3(cj)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxyethyl)oxy]methyl}azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.51 (s, 1H), 7.39 (dd, 1H), 7.35-7.31 (m, 1H),7.14-7.11 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.59 (m, 1H), 4.21-4.05 (brm, 4H), 3.77 (m, 2H), 3.66 (m, 2H); MS (EI) for C₁₉H₁₈F₃IN₂O₄: 523(MH⁺).

Example 3(ck)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1S,2S)-2-hydroxycyclohexyl]amino}methyl)azetidin-3-ol):MS (EI) for C₂₃H₂₅F₃IN₃O₃: 576 (MH⁺).

Example 3(cm)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1,1-dimethyl-2-pyrrolidin-1-ylethyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, CDCl₃):

8.49 (s, 1H), 7.39 (dd, 1H), 7.34-7.29 (m, 1H), 7.14-7.11 (m, 1H),6.83-6.77 (m, 1H₃), 6.64-6.59 (m, 1H), 4.25-4.07 (br m, 4H), 2.88 (d,2H), 2.62 (m, 4H), 2.58 (m, 2H), 1.78 (m, 4H), 2.05 (AcOH; s, 3H); MS(EI) for C₂₅H₃₀F₃IN₄O₂: 603 (MH⁺).

Example 3(cn)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1-methyl-1H-imidazol-4-yl)methyl]amino}methyl)azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.50 (s, 1H), 7.41-7.11 (m, 3H), 7.12 (m, 1H),6.85-6.79 (m, 2H), 4.12-3.98 (br m, 413), 3.78 (s, 2H), 3.66 (s, 3H),2.95 (s, 2H), 2.08 (AcOH; s, 4H), 2.05 (AcOH; s, 3H); MS (EI) forC₂₂H₂₁F₃IN₅O₂: 572 (MH⁺).

Example 3(co)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1-methyl-1H-imidazol-5-yl)methyl]amino}methyl)azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.45 (s, 1H), 7.47 (s, 1H), 7.39 (dd, 1H),7.33-7.30 (m, 1H), 7.15-7.10 (m, 1H), 6.91 (s, 1H), 6.87-6.77 (m, 1H),6.63-6.58 (m, 1H), 4.18-4.02 (m, 4H), 3.3.80 (s, 2H), 3.62 (s, 3H), 2.90(s, 1H), 2.05 (AcOH; s, 3H); MS (EI) for C₂₂H₂₁F₃IN₅O₂: 572 (MH⁺).

Example 3(cp)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(2S)-2-(methyloxy)cyclopentyl]amino}methyl)azetidin-3-ol):MS (EI) for C₂₃H₂₅F₃IN₃O₃: 576 (MH⁺).

Example 3(cq)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1R)-2-hydroxycyclohexyl]amino}methyl)azetidin-3-ol):MS (EI) for C₂₃H₂₅F₃IN₃O₃: 576 (MH⁺).

Example 3(cr)

N-[3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)phenyl]methanesulfonamide:¹H NMR (400 MHz, CDCl₃): 7.33 (dd, 1H), 7.22 (m, 1H), 7.08 (dd, 1H),6.83-6.77 (m, 1H), 6.03-5.98 (m, 2H), 6.64-6.59 (m, 1H), 4.08-3.77 (brm, 5H), 2.88 (s, 3H); MS (EI) for C₂₄H₂₂F₃IN₄O₄S: 647 (MH⁺).

Example 3(cs)

3-{[(4-aminophenyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:¹H NMR (400-MHz, CDCl₃): 8.44 (s, 1H), 7.39 (dd, 1H), 7.34-7.30 (m, 1H),7.14-7.10 (m, 1H), 6.84-6.77 (m, 1H), 6.64-6.53 (m, 5H), 4.22-4.04 (brin, 4H), 3.34 (s, 2H); MS (EI) for C₂₃H₂₀F₃IN₄O₂: 569 (MH⁺).

Example 3(ct)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxy-2-methylcyclopentyl)amino]methyl}azetidin-3-ol:MS (EI) for C₂₃H₂₅F₃IN₃O₃: 576 (MH⁺).

Example 3(cu)

3-[(cyclopentylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:¹H NMR (400 MHz, CD₃OD): 7.44 (dd, 1H), 7.36-7.31 (m, 1H), 7.30-7.24 (m,1H), 7.09-6.99 (m, 1H), 6.64-6.57 (m, 1H), 4.17-4.10 (m, 1H), 4.01-3.91(m, 2H), 3.87-3.79 (m, 1H), 3.07-2.97 (m, 1H), 2.75 (s, 2H), 1.92-1.79(m, 2H), 1.75-1.62 (m, 2H), 1.61-1.47 (m, 2H), 1.37-1.22 (m, 2H). MS(EI) for C₂₂H₂₃F₃IN₃O₂: 546 (MH⁺).

Example 3(cv)

3-{[(cyclohexylmethyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ylacetate (salt): ¹H NMR (400 MHz, CD₃OD): 7.46 (dd, 1H), 7.39-7.32 (m,1H), 7.31-7.25 (m, 1H), 7.11-6.99 (m, 1H), 6.67-6.57 (in, 1H), 4.27-4.15(m, 1H), 4.12-3.97 (m, 2H), 3.96-3.85 (m, 1H), 3 (s, 2H), 2.62 (d, 2H),1.90 (s, 3H), 1.82-1.45 (m, 6H), 1.40-1.07 (m, 3H), 1.04-0.80 (m, 21).MS (EI) for C₂₄H₂₇F₃IN₃O₂: 574 (MH⁺).

Example 3(cw)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(propylamino)methyl]azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): δ 8.56 (s, 1H), 7.57 (dd, 1H), 7.37 (dd, 1H),7.32 (m, 1H), 7.18 (m, 1H), 6.67 (m, 1H), 4.03 (d, 1H), 3.89 (m, 2H),3.69 (d, 1H), 2.59 (s, 2H), 2.42 (t, 2H), 1.90 (s, 3H), 1.32 (m, 2H),0.81 (t, 3H); MS (EI) for C₂H₂₁F₃IN₃O₂: 520 (MH⁺).

Example 3(cx)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-methylpropyl)amino]methyl}azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): δ 8.56 (s, 1H), 7.56 (dd, 1H), 7.36 (dd, 1H),7.31 (m, 1H), 7.18 (m, 1H), 6.67 (m, 1H), 4.02 (d, 1H), 3.89 (m, 2H),3.70 (d, 1H), 2.57 (s, 2H), 2.27 (d, 2H), 1.91 (s, 3H), 1.55 (m, 1H),0.79 (d, 6H); MS (EI) for C₂₁H₂₃F₃IN₃O₂: 534 (MH⁺).

Example 3(cy)

methyl(2xi)-2-deoxy-2-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)-beta-D-arabino-hexopyranoside:¹H NMR (400 MHz, d₄-methanol, ˜3:1 mixture of anomers): δ 7.46 (d, 1H),7.34 (d, 1H), 7.28 (m, 1H), 7.04 (q, 1H), 6.62 (m, 1H), 4.19-5.92 (m,4H), 3.87-3.78 (m, 2H), 3.68 (m, 1H), 3.56-3.18 (m, 5H), 2.99-2.82 (m,3H), 2.56 (m, 0.25H), 2.29 (m, 0.75H) MS (EI) for C₂₄H₂₇F₃IN₃O₇: 652(M-H).

Example 3(cz)

3-({[3-(diethylamino)propyl]amino}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.38-7.33 (d,1H), 7.32-7.26 (m, 1H), 7.09-7.00 (q, 1H), 6.66-6.58 (t, 1H), 4.24-4.16(d, 1H), 4.11-3.99 (t, 2H), 3.92-3.85 (d, 1H), 3.10-3.02 (m, 8H),2.99-2.96 (s, 2H), 2.92-2.87 (t, 2H), 1.93-1.87 (s, 3H), 1.27-1.20 (t,6H); MS (EI) for C₂₄H₃₀F₃IN₄O₂: 591 (MH⁺).

Example 41-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2-hydroxyethyl)azetidine-3-carboxamide

To a solution of1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxylicacid (15 mg, 0.03 mmol), prepared using procedures similar to those inExample 1, in N,N-dimethylformamide (2.00 mL) was added HBTU (38 mg,0.10 mmol). The mixture was stirred for 15 minutes at room temperaturefollowed by the addition of 2-aminoethanol (3.6 μL, 0.06 mmol) andN-methylmorpholine (110 μL, 1.00 mmol). The mixture was allowed to stirat room temperature for 3 d, then diluted the mixture with chloroform(20 mL), and washed with water (30 mL). The aqueous phase was backextracted with chloroform (10 mL). The combined organic phases weredried over sodium sulfate, filtered and the filtrate concentrated invacuo. The residue was purified by high pressure liquid chromatographyto afford the title compound (9.20 mg, 58%) as the trifluoroacetic acidsalt: ¹H NMR (400 MHz, CDCl₃): 8.54 (s, 1H), 7.41-7.37 (m, 1H),7.34-7.31 (m, 1H), 7.18-7.14 (m, 1H), 6.85-6.77 (m, 1H), 6.64-6.58 (m,1H), 4.66 (br, 1H), 4.40-4.24 (br, 3H), 3.83-3.23 (br m, 7H), 1.18 (t,3H); MS (EI) for C₁₉H₁₇F₃IN₃O₃: 542 (MNa⁺).

Using the same or analogous synthetic techniques and substituting, asnecessary, with alternative reagents, the following compounds of theinvention were prepared:

Example 4(a)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(3,4-dihydroxybutyl)azetidine-3-carboxamide:¹H NMR (400 MHz, CDCl₃): 8.55 (s, 1H), 7.40 (dd, 1H), 7.31-7.35 (m, 1H),7.14-7.18 (m, 1H), 6.78-6.84 (m, 1H), 6.59-6.65 (m, 1H), 6.14 (br s,1H), 4.50-4.60 (m, 1H), 4.20-4.40 (m, 3H), 3.60-3.80 (m, 3H), 3.40-3.52(m, 2H), 3.20-3.32 (m, 2H), 1.96 (br s, 1H), 1.18-1.28 (m, 2H). MS (EI)for C₂₁H₂₁F₃IN₃O₄: 562 (M−H).

Example 4(b)

N-butyl-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxamide:¹H NMR (400 MHz, CDCl₃): 8.53 (s, 1H), 7.39 (dd, 1H), 7.33-7.31 (m, 1H),7.17-7.13 (m, 1H), 6.83-6.77 (m, 1H), 6.64-6.58 (m, 1H), 5.50 (m, 1H),4.57 (br, 1H), 4.29 (br m, 3H), 3.27 (m, 3H), 1.49 (m, 1H), 1.33 (m,2H), 0.92 (t, 3H); MS (EI) for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺), 554 (MNa⁺).1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-prop-2-en-1-ylazetidine-3-carboxamide:¹H NMR (400 MHz, CDCl₃): 8.54 (s, 1H), 7.39 (dd, 1H), 7.34-7.31 (m, 1H),7.17.7.12 (m, 1H), 6.83-6.77 (m, 1H), 6.64-6.58 (m, 1H), 5.88-5.77 (m,1H), 5.57 (br, 1H), 5.21-5.16 (m, 2H), 4.59 (br, 1H), 4.30 (br m, 3H),3.9 (tt, 2H), 3.32-3.25 (m, 1H)); MS (EI) for C₂₀H₁₇F₃IN₃O₂: 516 (MH⁺),538 (MNa⁺).

Example 4(c)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-ethylazetidine-3-carboxamide:¹H NMR (400 MHz, CDCl₃): 8.54 (s, 1H), 7.38 (dd, 1H), 7.33-7.30 (m, 1H),7.17-7.12 (m, 1H), 6.83-6.77 (m, 1H), 6.63-6.57 (m, 1H), 5.55 (br s,1H), 4.57 (br s, 1H), 4.28 (br m, 1H), 3.36-3.29 (m, 2H), 3.27-3.20 (m,1H), 1.15 (t, 3H); MS (EI) for C₁₉H₁₇F₃IN₃O₂: 504 (MH⁺), 526 (MNa⁺).

Example 4(d)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2-hydroxyethyl)azetidine-3-carboxamide:¹H NMR (400 MHz, CDCl₃): 8.50 (s, 1H), 7.39 (dd, 1H), 7.33-7.30 (m, 1H),7.16-7.12 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.57 (br, 1H),4.28 (br, 3H), 3.73 (t, 2H), 3.49-3.44 (m, 2H), 3.33-3.27 (m, 1H), 2.18(br, 1H); MS (EI) for C₁₉H₁₇F₃IN₃O₃: 542 (MNa⁺).

Example 4(e)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2-piperidin-1-ylethyl)azetidine-3-carboxamide:¹H NMR (400 MHz, CDCl₃): 11.28 (s, 1H), 8.55 (s, 1H), 7.38 (dd, 1H),7.33-7.30 (m, 1H), 7.15-7.10 (m, 1H), 6.82-6.76 (m, 1H), 6.63-6.58 (m,1H), 4.42 (b, 1H), 4.26 (br m, 3H), 3.68 (br s, 2H), 3.58 (br d, 2H),3.36 (br m, 1H) 3.17 (br s, 1H), 2.63 (m, 4H), 1.92 (m, 5H); MS (EI) forC₂₄H₂₃F₃IN₄O₂: 587 (MH⁺).

Example 4(f)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-phenylazetidine-3-carboxamide:¹H NMR (400 MHz, CDCl₃): 8.52 (s, 1H), 7.50 (d, 1H), 7.41-7.27 (m, 4H),7.16 (m, 2H), 6.85-6.78 (m, 1H), 6.65-6.59 (m, 1H), 4.37 (br, 3H), 3.43(m, 1H); MS (EI) for C₂₃H₁₇F₃IN₃O₂: 574 (MNa⁺).

Example 4(g)

N-[2-(diethylamino)ethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxamide:¹H NMR (400 MHz, CDCl₃): 11.43 (s, 1H), 8.90 (s, 1H), 8.55 (s, 1H), 7.39(dd, 1H), 7.33-7.30 (m, 1H), 7.15-7.10 (m, 1H), 6.87-6.77 (m, 1H),6.63-6.58 (m, 1H), 4.44-4.22 (m, 4H), 3.65 (m, 2H), 3.38 (m, 1H),3.19-3.13 (m, 5H), 1.33 (t, 6H); MS (EI) for C₂₁H₂₁F₃IN₃O₂: 575 (MH⁺).

Example 4(h)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-[(2,3-dihydroxypropyl)oxy]azetidine-3-carboxamide:MS (EI) for C₂₀H₁₉F₃IN₃O₅: 566 (MH⁺).

Example 4(i)

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2,3-dihydroxypropyl)azetidine-3-carboxamide:¹H NMR (400 MHz, CDCl₃): 8.40 (br s, 1H), 7.35 (dd, 1H), 7.30 (br d,1H), 7.16-7.09 (m, 1H), 6.89-6.76 (m, 2H), 6.58 (ddd, 1H), 4.58-4.40(br, 1H), 4.27 (br t, 21H), 4.22-4.14 (br, 1H), 4.08-3.12 (m, 5H),2.18-1.82 (br, 2H); MS (EI) for C₂₀H₁₉F₃IN₃O₄: 550 (MH⁺).

Example 4(j)

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-hydroxyazetidine-3-carboxamide:¹H NMR (400 MHz, CDCl₃): 8.23-8.10 (b, 1H), 7.35-7.28 (m, 2H), 7.14-7.07(m, 1H), 6.86-6.80 (m, 1H), 6.60-6.54 (m, 1H), 4.52-4.38 (b, 1H),4.32-4.08 (m, 3H), 3.30-3.21 (m, 1H); MS (EI) for C₁₇H₁₃F₃IN₃O₃: 492(MH⁺).

Example 56-({3-[dimethylamino)methyl]azetidin-1-yl}carbonyl)-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline

A mixture of1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxylicacid (196 mg, 0.41 mmol), prepared using procedures similar to those inExample 1, triethylamine (58 μL, 0.41 mmol), PyBOP (213 mg, 0.41 mmol)and sodium borohydride (48 mg, 124 mmol) in tetrahydrofuran (2 mL) wasstirred at room temperature for 15 hours. The reaction mixture wasconcentrated in vacuo and the resultant residue was partitioned between20% aqueous citric acid and ethyl acetate. The organic portion waswashed with brine, dried over sodium sulfate, filtered and concentratedin vacuo to afford a colorless residue that was purified by columnchromatography. Eluting with 60% ethyl acetate in hexanes, isolatedproduct was concentrated in vacuo to afford 48 mg, 0.11 mmol (25%) of[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]methanolas a white solid. ¹H NMR (400 MHz, CDCl₃): 7.44 (d, 1H), 7.34 (d, 1H),7.28-7.23 (m, 1H), 7.04-6.97 (m, 1H), 4.26-4.18 (m, 1H), 4.02-3.94 (m,2H), 3.78-3.72 (m, 1H), 3.03 (d, 2H), 3.34 (s, 1H), 2.80-2.71 (m, 1H).MS (EI) for C₁₇H₁₄F₃IN₂O: 463 (MH⁺).

A solution of1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]methanol(48 mg, 0.11 mmol), 1,4-diazabicyclo[2.2.2]octane (18 mg, 0.16 mmol) andmethanesulfonyl chloride (10 μL, 0.13 mmol) in tetrahydrofuran (2 mL)was stirred at room temperature for 15 minutes. The mixture was thenpartitioned between water and ethyl acetate. The organic portion waswashed with brine, dried over sodium sulfate, filtered and concentratedin vacuo to afford a colorless residue which was purified by columnchromatography. Eluting with 70% ethyl acetate in hexanes, isolatedproduct was concentrated in vacuo to afford 28 mg, 0.05 mmol (47%) of[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]methylmethanesulfonate as a colorless residue which was immediately dissolvedin ethylene glycol dimethyl ether (2 mL). To the solution was addeddimethylamine (excess) and the solution was stirred in a seal tube at50° C. for 15 hours. The reaction mixture was concentrated in vacuo, andthe resultant residue was purified by preparative reverse phase HPLC.Isolated product was concentrated in vacuo to afford 12 mg, 0.02 mmol(40%) of6-({3-[dimethylamino)methyl]azetidin-1-yl}carbonyl)-2,3-difluoro-N-(2-fluoro-4-iodophenyl)anilineacetate salt as a white solid. ¹H NMR (400 MHz, DMSO): 8.54 (br s, 1H),7.58 (d, 1H), 7.37 (d, 1H), 7.33-7.28 (m, 1H), 7.18-7.12 (m, 1H),6.70-6.64 (m, 1H), 4.18-4.12 (m, 1H), 3.99-3.76 (m, 1H), 3.52-3.47 (m,1H), 2.52-2.48 (m, 1H), 2.39 (d, 2H), 1.85 (s, 6H); MS (EI) forC₁₉H₁₉F₃IN₃O: 490 (MH⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative reagents, the following compounds of the invention wereprepared:

Example 5(a)

2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-[(3-{[(1-methylethyl)amino]methyl}azetidin-1-yl)carbonyl]aniline:¹H NMR (400 MHz, CDCl₃): 8.54 (s, 1H), 7.40 (dd, 1H), 7.31-7.33 (m, 1H),7.11-7.15 (m, 1H), 6.76-6.82 (m, 1H), 6.58-6.64 (m, 1H), 4.23-4.30 (m,2H), 3.90-4.00 (m, 1H), 3.76-3.84 (m, 1H), 2.69-2.85 (m, 4H), 1.05 (d,6H). MS (EI) for C₂₀H₂₁F₃IN₃O: 502 (M-H).

Example 5(b)

2-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-2-yl]methyl}amino)ethanol:MS (EI) for C₁₉H₁₉F₃IN₃O₂: 506 (MH⁺).

Example 5(c)

N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-2-yl]methyl}ethane-1,2-diamine:MS (EI) for C₁₉H₂₀F₃IN₄O: 505 (MH⁺).

Example 5(d)

6-({3-[dimethylamino)methyl]azetidin-1-yl}carbonyl)-2,3-difluoro-N-(2-fluoro-4-iodophenyl)anilineacetate salt: ¹H NMR (400 MHz, DMSO): 8.54 (br s, 1H), 7.58 (d, 1H),7.37 (d, 1H), 7.33-7.28 (m, 1H), 7.18-7.12 (m, 1H), 6.70-6.64 (m, 1H),4.18-4.12 (m, 1H), 3.99-3.76 (m, 1H), 3.52-3.47 (m, 1H), 2.52-2.48 (m,1H), 2.39 (d, 2H), 1.85 (s, 6H); MS (EI) for C₁₉H₁₉F₃IN₃O: 490 (MH⁺).

Example 61-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol(132 mg, 0.295 mmol)ures similar to those in Example 1, was dissolved indichloromethane (8 mL) and cooled to 0° C. Dess-Martin periodinane (187mg, 0.441 mmol) was added and the mixture was stirred at ambient for 2h. The mixture was quenched with saturated sodium bicarbonate solution:10% sodium thiosulfate solution (1:1; 6 mL) and diluted with ethylacetate. The organic portion was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. Columnchromatography (silica gel, 40-50% ethyl acetate in hexanes) gave1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one(122 mg, 0.273 mmol, 93% yield): ¹H NMR (400 MHz, CDCl₃): 8.43 (br s,1H), 7.44-7.38 (m, 1H), 7.36-7.32 (m, 1H), 7.27-7.20 (m, 1H), 6.86 (ddd,1H), 6.64 (ddd, 1H), 4.94-4.93 (m, 4H); MS (EI) for C₁₆H₁₀F₃IN₂O₂: 447(MH⁺).

Example 71-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(hydroxymethyl)azetidin-3-ol

Methyl triphenylphosphonium bromide (508 mg, 1.42 mmol) was treated withpotassium tert-butoxide (159 mg, 1.42 mmol) in tetrahydrofuran (5 mL) at0° C. for 10 minutes.1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one(270 mg, 0.605 mmol), prepared using procedures similar to thosedescribed in Example 6, was dissolved in tetrahydrofuran (2 mL) and wasadded to the mixture. The mixture was stirred at ambient for 15 h andthen the mixture was filtered and the filtrate was partitioned betweenethyl acetate and water. The aqueous portion was extracted with ethylacetate. The combined organic portion was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Columnchromatography (silica gel, 20% ethyl acetate in hexanes) gave2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-[(3-methylideneazetidin-1-yl)carbonyl]aniline(57 mg, 0.128 mmol, 21% yield): ¹H NMR (400 MHz, CDCl₃): 8.56 (br s,1H), 7.39 (dd, 1H), 7.35-7.30 (m, 1H), 7.18-7.12 (m, 1H), 6.86-6.76 (m,1H), 6.62 (ddd, 1H), 5.14-5.00 (br, 2H), 4.74 (br d, 4H); MS (EI) forC₁₇H₁₂F₃IN₂O: 445 (MH⁺).

2,3-Difluoro-N-(2-fluoro-4-iodophenyl)-6-[(3-methylidencazetidin-1-yl)carbonyl]aniline(56 mg, 0.126 mmol) and 4-methylmorpholine N-oxide (44 mg, 0.376 mmol)were dissolved in acetone/water (4:1; 10 mL) and osmium tetroxide (4 wt.% in water; 0.7 mL) was added. The solution was stirred at ambient for 4h, then was quenched with saturated sodium bisulfite (2 mL) andconcentrated in vacuo. The residue was partitioned between ethyl acetateand water. The organic portion was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Columnchromatography (silica gel, 80% ethyl acetate in hexanes) and thenreverse phase HPLC gave1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(hydroxymethyl)azetidin-3-ol(17 mg, 0.036 mmol, 28% yield): ¹H NMR (400 MHz, CDCl₃): 8.43 (br s,1H), 7.40 (dd, 1H), 7.35-7.31 (m, 1H), 7.16-7.10 (m, 1H), 6.81 (ddd,1H), 6.61 (ddd, 1H), 4.25-4.00 (m, 4H), 3.78 (s, 2H); MS (EI) forC₁₇H₁₄F₃IN₂O₃: 479 (MH⁺).

Example 8

3-(2-aminopyrimidin-4-yl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol

To a solution of 4-iodo-2-(methylthio)pyrimidine (2.00 g, 7.92 mmol) intetrahydrofuran (4.00 ml) was added isopropylmagnesium chloride (815 mg,7.92 mmol). The mixture was allowed to stir for 1 h at 0° C., followedby the addition of 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (1.64g, 9.60 mmol), prepared using procedures similar to those described inExample 3. The reaction mixture was then allowed to warm to roomtemperature and stirred for 6 h. The mixture was quenched with 1 Nhydrochloric acid (10 mL) and extracted with ethyl acetate. The organiclayer was separated, dried over anhydrous sodium sulfate, filtered andthe filtrate concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, hexanes/ethyl acetate) to afford 1,1-dimethylethyl3-hydroxy-3-[2-(methylthio)pyrimidin-4-yl]azetidine-1-carboxylate (380mg, 16%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): 8.62-8.59 (d, 1H),7.36-7.33 (d, 1H), 5.14-5.11 (s, 1H), 4.29-4.24 (d, 2H), 4.13-4.08 (d,2H), 2.61-2.58 (s, 3H), 1.50-1.47 (s, 9H); MS (EI) for C₁₃H₁₉N₃O₃S: 298(MH⁺).

A solution of 1,1-dimethylethyl3-hydroxy-3-[2-(methylthio)pyrimidin-4-yl]azetidine-1-carboxylate (480mg, 1.62 mmol), and 3-chloroperoxybenzoic (558 mg, 3.23 mmol) acid indichloromethane (25 mL) was stirred at room temperature for 22 h. Thereaction mixture was quenched with a saturated solution of sodiumthiosulfate and the pH adjusted to 7 with sodium carbonate. The organiclayer was separated, dried over anhydrous sodium sulfate, filtered andthe filtrate concentrated in vacuo. The resulting crude1,1-dimethylethyl3-hydroxy-3-[2-(methylsulfonyl)pyrimidin-4-yl]azetidine-1-carboxylate(524 mg, 98%) was used without further purification. ¹H NMR (400 MHz,CDCl₃): 9.01-8.97 (d, 1H), 7.96-7.93 (d, 1H), 4.57-4.53 (s, 1H),4.31-4.27 (d, 2H), 4.23-4.18 (d, 2H), 3.42-3.39 (s, 3H), 1.50-1.47 (s,9H); MS (EI) for C₁₃H₁₉N₃O₅S: 330 (MH⁺).

A solution of 1,1-dimethylethyl3-hydroxy-3-[2-(methylsulfonyl)pyrimidin-4-yl]azetidine-1-carboxylate(215 mg, 0.652 mmol), and aqueous ammonia (7 mL, 28% solution) indioxane (15 mL) within a sealed steel bomb cylinder was heated at 80° C.for 4 h. The mixture was cooled to room temperature and the solvent wasevaporated. The residue was dissolved in dichloromethane and a solutionof saturated sodium carbonate. The organic layer was separated, driedover anhydrous sodium sulfate, filtered and the filtrate concentrated invacuo. The resulting crude 1,1-dimethylethyl3-(2-aminopyrimidin-4-yl)-3-hydroxyazetidine-1-carboxylate (140 mg,100%) was used without further purification. ¹H NMR (400 MHz, CDCl₃):8.38-8.35 (d, 1H), 6.97-6.94 (d, 1H), 5.30-5.28 (s, 2H), 4.23-4.18 (d,2H), 4.08-4.04 (d, 2H), 1.48-1.45 (s, 9H).

To a solution of 1,1-dimethylethyl3-(2-aminopyrimidin-4-yl)-3-hydroxyazetidine-1-carboxylate (140 mg,0.524 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (3ml). The reaction mixture was stirred for 2 h at room temperature. Themixture was concentrated in vacuo. The resulting crude3-(2-aminopyrimidin-4-yl)azetidin-3-ol (87 mg, 100%) was used withoutfurther purification.

A solution of 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid(201 mg, 0.512 mmol), prepared using procedures similar to thosedescribed in U.S. Pat. No. 7,019,033,3-(2-aminopyrimidin-4-yl)azetidin-3-ol (87 mg, 0.52 mmol),benzotriazol-1-yl-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate(293 mg, 0.563 mmol) and N,N-diisopropylethylamine (270 uL, 2.82 mmol)in N,N-dimethylformamide (2 mL) was stirred at room temperature for 20h. The mixture was partitioned between ethyl acetate and saturatedsodium bicarbonate. The organic layer was separated and washed withbrine, dried over sodium sulfate, filtered and the filtrate concentratedin vacuo. The residue was purified by reverse phase HPLC to afford thetitle compound3-(2-aminopyrimidin-4-yl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol(22 mg, 7%). ¹H NMR (400 MHz, CD₃OD): 8.23-8.20 (d, 1H), 7.48-7.43 (d,1H), 7.35-7.32 (m, 2H), 7.09-7.00 (m, 1H), 6.88-6.84 (d, 1H), 6.70-6.63(t, 1H), 4.59-4.54 (d, 1H), 4.45-4.40 (d, 1H), 4.23-4.18 (d, 1H),3.04-3.99 (t, 1H); MS (EI) for C₂₀H₁₅F₃IN₅O₂: 542 (MH⁺).

Using the same or analogous synthetic techniques and substituting, asnecessary, with alternative reagents, the following compounds of theinvention were prepared:

Example 8(a)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-pyridin-2-ylazetidin-3-ol:¹H NMR (400 MHz, CD₃OD): 8.47 (m, 1H), 7.80 (m, 1H), 7.65 (d, 1H), 7.44(m, 1H), 7.33 (m, 3H), 7.04 (m, 1H), 6.65 (m, 1H), 4.61 (d, 1H), 4.44(d, 1H), 4.29 (d, 1H), 4.12 (d, 1H). MS (EI) for C₂₁H₁₅F₃IN₃O₂: 526(MH⁺).

Example 8(b)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1H-imidazol-2-yl)azetidin-3-ol:¹H NMR (400 MHz, CD₃OD): 7.42 (m, 1H), 7.37 (m, 1H), 7.32 (m, 1H), 7.02(m, 3H), 6.63 (m, 1H), 4.65 (d, 1H), 4.42 (d, 1H), 4.33 (d, 1H), 4.16(d, 1H). MS (EI) for C₁₉H₁₄F₃IN₄O₂: 515 (MH⁺).

Example 8(c)

3-(1H-benzimidazol-2-yl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:¹H NMR (400 MHz, CD₃OD): 7.55 (br s, 2H), 7.42 (m, 2H), 7.33 (m, 1H),7.23 (m, 2H), 7.04 (m, 1H), 6.65 (m, 1H), 4.76 (d, 1H), 4.57 (d, 1H),4.43 (d, 1H), 4.25 (d, 1H). MS (EI) for C₂₃H₆F₃IN₄O₂: 565 (MH⁺).

Example 8(d)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(5-methyl-1H-imidazol-2-yl)azetidin-3-ol:¹H NMR (400 MHz, CD₃OD): 7.41 (m, 1H), 7.36 (m, 1H), 7.31 (m, 1H), 7.02(m, 1H), 6.67 (br s, 1H), 6.63 (m, 1H), 4.63 (d, 1H), 4.39 (d, 1H), 4.30(d, 1H), 4.13 (d, 1H), 2.18 (s, 3H). MS (EI) for C₂₀H₁₆F₃IN₄O₂: 529(MH⁺).

Example 8(e)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-prop-2-en-1-ylazetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.47 (br s, 1H), 7.40 (dd, 1H), 7.35-7.31 (m,1H), 7.15-7.10 (m, 1H), 6.81 (ddd, 1H), 6.62 (ddd, 1H), 5.84-5.72 (m,1H), 5.27-5.20 (m, 2H), 4.22-3.94 (m, 4H), 2.52 (d, 2H), 2.25 (s, 1H);MS (EI) for C₁₉H₁₆F₃IN₂O₂: 489 (MH⁺).

Example 8(f)

3-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]propane-1,2-diol:¹H NMR (400 MHz, CDCl₃): 8.43 (br s, 1H), 7.39 (dd, 1H), 7.35-7.30 (m,1H), 7.16-7.10 (m, 1H), 6.82 (ddd, 1H), 6.61 (ddd, 1H), 4.31-3.91 (m,5H), 3.68 (br d, 1H), 3.54-3.49 (m, 1H), 2.01-1.80 (m, 2H); MS (EI) forC₁₉H₁₈F₃IN₂O₄: 523 (MH⁺).

Example 8(g)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-ethenylazetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.48 (br s, 1H), 7.40 (dd, 1H), 7.35-7.31 (m,1H), 7.17-7.11 (m, 1H), 6.81 (ddd, 1H), 6.62 (ddd, 1H), 6.15 (dd, 1H),5.39 (d, 1H), 5.28 (d, 1H)), 4.30-4.10 (m, 4H); MS (EI) for C₁₈H₁₄F₃NO₂:475 (MH⁺).

Example 8(h)

1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethane-1,2-diolhydrochloride: ¹H NMR (400 MHz, d₆-DMSO): 8.66 (d, 1H), 7.58 (dd, 1H),7.38 (d, 1H), 7.33-7.27 (m, 1H), 7.17 (q, 1H), 6.74-6.65 (m, 1H),4.50-3.58 (br, 3H), 4.29 (dd, 1H), 4.14 (dd, 1H), 3.87 (t, 1H), 3.66 (t,1H), 3.56-3.32 (m, 3H); MS (EI) for C₁₈H₁₆F₃IN₂O₄: 509 (MH⁺).

Example 8(i)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-ethylazetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.23 (br s, 1H), 7.40 (d, 1H), 7.33 (d, 1H),7.15-7.10 (m, 1H), 6.85-6.79 (m, 1H), 6.64-6.58 (m, 1H), 4.14-3.94 (m,4H), 1.78 (q, 2H), 0.96 (t, 3H); MS (EI) for C₁₈H₁₆F₃IN₂O₂: 477 (MH⁺).

Example 8(j)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-methylazetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.31 (br s, 1H), 7.40 (d, 1H), 7.33 (d, 1H),7.15-7.11 (m, 1H), 6.85-6.78 (m, 1H), 6.65-6.59 (m, 1H), 4.24-4.04 (m,4H), 1.55 (s, 3H); MS (EI) for C₁₇H₁₄F₃IN₂O₂: 463 (MH⁺).

Example 8(k)

3-(2-aminopyrimidin-4-yl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 8.22-8.20 (d, 1H), 7.48-7.43 (d,1H), 7.38-7.30 (m, 1H), 7.09-7.01 (q, 1H), 6.88-6.84 (d, 1H), 6.70-6.61(t, 1H), 4.59-4.54 (d, 1H), 4.44-4.39 (d, 1H), 4.23-4.19 (d, 1H),4.05-3.99 (d, 1H), 3.90-3.81 (d, 1H), 1.99-1.97 (s, 3H); MS (EI) forC₂₀H₁₅F₃IN₅O₂: 542 (MH⁺).

Example 8(m)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1H-pyrrol-2-yl)azetidin-3-ol:¹H NMR (400 MHz, CD₃OD): 7.37 (dd, 1H), 7.31-7.23 (m, 2H), 7.07-6.97 (m,1H), 6.73-6.68 (m, 1H), 6.65-6.56 (m, 1H), 6.06-5.98 (m, 2H), 4.49-4.40(m, 1H), 4.32-4.18 (m, 2H), 4.15-88-4.07 (m, 1H). MS (EI) forC₂₀H₁₅F₃IN₃O₂: 514 (MH⁺).

Example 8(n)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-methyl-1H-imidazol-2-yl)azetidin-3-ol:¹H NMR (400 MHz, CD₃OD): 7.34 (dd, 1H), 7.31-7.25 (m, 1H), 7.23-7.18 (m,1H), 7.11-7.09 (m, 1H), 7.06-6.97 (m, 1H), 6.89-6.86 (m, 1H), 6.62-6.55(m, 1H), 4.88-4.80 (m, 1H), 4.52-4.44 (m, 1H), 4.38-4.30 (m, 1H),4.21-4.12 (m, 1H), 3.68 (s, 3H). MS (EI) for C₂₀H₁₆F₃IN₄O₂: 529 (MH⁺).

Example 91-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(trifluoromethyl)azetidin-3-ol

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one(25 mg, 0.056 mmol), prepared using procedures described in Example 6,was taken into DMF (0.5 mL) followed by addition of(trifluoromethyl)trimethylsilane (40 μL, 0.28 mmol) and cesium carbonate(22 mg, 0.067 mmol) and the mixture was stirred for one hour at roomtemperature. The mixture was partitioned with ethyl ether and water andthe organic phase washed three times with additional water then brineand dried over anhydrous sodium sulfate. Filtration and concentrationfollowed by silica gel flash chromatography of the residue usinghexanes:ethyl acetate 3:2 as eluent afforded1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(trifluoromethyl)azetidin-3-ol(19.8 mg, 69% yield) as a colorless crystalline solid. ¹H-NMR (400 MHz,CDCl₃): 8.31-8.26 (br, 1H), 7.40 (d, 1H), 7.33 (d, 1H), 7.13-7.10 (m,1H), 6.86-6.80 (m, 1H), 6.65-6.60 (m, 1H), 4.42 (br s, 2H), 4.18 (br s,2H). MS (EI) for C₁₇H₁₁F₆N₂O₂: 517 (MH⁺).

Example 101-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-oneOxime

To a solution of1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one(100 mg, 0.22 mmol), prepared using procedures similar to thosedescribed in Example 6, in dioxane (1.0 mL) was added hydroxylamine(0.10 mL, 50% solution in water, 1.5 mmol), and the resulting solutionwas heated at 60° C. for 18 h. The mixture was cooled to roomtemperature and the crude product was purified by reverse phase HPLC toafford1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-oneoxime (56 mg, 54% yield): ¹HNMR (400 MHz, CDCl₃), 8.43 (br s), 7.43-7.39(m, 2H), 7.35-7.32 (dd, 1H), 7.19-7.15 (m, 1H), 6.87-6.81 (m, 1H),6.65-6.59 (m, 1H), 4.89 (br s, 2H), 4.85 (br s, 2H); MS (EI) forC₁₆H₁₁F₃IN₃O₂: 462 (MH⁺).

Example 11N-butyl-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine

To a solution of1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine(0.09 M in acetonitrile, 500 μL, 0.045 mmol), prepared using proceduressimilar to those described in Example 2, was added triethylamine (20 μL,0.135 mmol) and n-butylbromide (6.14 μL, 0.054 mmol) followed byadditional acetonitrile (1.0 mL). The reaction mixture was stirred atroom temperature for 16 h, at which time it was purified directly byreverse phase HPLC to afford the title compound (8.4 mg). ¹H NMR (400MHz, CDCl₃): 8.50 (s, 1H), 7.39 (dd, 1H), 7.32 (dd, 1H), 7.13-7.09 (m,1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.35 (br s, 2H), 4.00 (br s,1H), 3.87 (br s, 1H), 3.74-3.68 (m, 1H), 3.20 (br s, 3.5H), 2.56 (t,2H), 2.03 (s, 2H), 1.50-1.42 (m, 2H), 1.39-1.29 (m, 2H), 0.91 (t, 3H).MS (EI) for C₂₀H₂₁F₃IN₃O: 504 (MH⁺).

Example 12

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-methylazetidin-3-amine

To a solution of1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine(0.10 M in acetonitrile, 1.0 mL, 0.09 mmol), prepared using proceduressimilar to those described in Example 2, in 1:1 ratio of methanol andtetrahydrofuran (2.0 mL) was added formaldehyde (37% wt, 6.7 μL, 0.09mmol) followed by sodium cyanoborohydride (11.0 mg, 0.18 mmol). Thereaction mixture was stirred at room temperature for 16 h, at which timeit was quenched with saturated aqueous ammonium chloride. The solutionwas then purified directly by reverse phase HPLC to afford the titlecompound (14.9 mg). ¹H NMR (400 MHz, CDCl₃): 8.13 (br s, 1H), 7.35 (d,1H), 7.30 (d, 1H), 7.09-7.04 (m, 1H), 6.84-6.78 (m, 1H), 6.60-6.54 (m,1H), 4.46-4.33 (br m, 4H), 3.93 (br m, 1H), 2.64 (s, 3H). MS (EI) forC₁₇H₁₅F₃IN₃O: 462 (MH⁺).

Using the same or analogous synthetic techniques and substituting, asnecessary, with alternative reagents, the following compounds of theinvention were prepared:

Example 12(a)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-methylazetidin-3-amine:¹H NMR (400 MHz, CDCl₃): 8.13 (br s, 1H), 7.35 (d, 1H), 7.30 (d, 1H),7.09-7.04 (m, 1H), 6.84-6.78 (m, 1H), 6.60-6.54 (m, 1H), 4.46-4.33 (brm, 4H), 3.93 (br m, 1H), 2.64 (s, 3H). MS (EI) for C₁₇H₁₅F₃IN₃O: 462(MH⁺).

Example 12(b)

2-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]amino}ethanol:¹H NMR (400 MHz, CDCl₃): 8.20 (s, 1H), 7.36 (d, 1H), 7.30 (d, 1H),7.13-7.09 (m, 1H), 6.85-6.79 (m, 1H), 6.61-6.55 (m, 1H), 4.43 (br m,3H), 3.98 (br m, 1H), 3.87 (br m, 1H), 3.02 (br m, 1H), 1.24-1.20 (m,1H). MS (EI) for C₁₈H₁₇F₃IN₃O₂: 492 (MH⁺).

Example 12(c)

N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]propane-1,3-diamine:¹H NMR (400 MHz, CDCl₃): 8.51 (s, 1H), 7.39 (d, 1H), 7.32 (d, 1H),7.14-7.10 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.33 (br s,2H), 3.99 (br s, 1H), 3.84 (br s, 1H), 3.71-3.64 (m, 1H), 2.91 (t, 2H),2.70-2.66 (m, 2H), 2.01 (s, 4H), 1.76-1.69 (m, 2H). MS (EI) forC₁₉H₂₀F₃IN₄O: 505 (MH⁺).

Example 12(d)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-ethylazetidin-3-amine:¹H NMR (400 MHz, CDCl₃): 8.47 (s, 1H), 7.38 (d, 1H), 7.31 (d, 1H),7.13-7.09 (m, 1H), 6.83-6.77 (m, 1H), 6.62-6.57 (m, 1H), 4.49 (br s,3H), 4.36 (br s, 2H), 4.08 (br s, 1H), 3.94 (br s, 1H), 3.77-3.72 (m,1H), 2.69-2.63 (m, 21H), 1.99 (s, 2H), 1.14 (t, 3H). MS (EI) forC₁₈H₁₇F₃IN₃O: 476 (MH⁺).

Example 12(c)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2-methylpropyl)azetidin-3-amine:¹H NMR (400 MHz, CDCl₃): 8.50 (s, 1H), 7.38 (d, 1H), 7.31 (d, 1H),7.14-7.09 (m, 1H), 6.83-6.76 (m, 1H), 6.63-6.57 (m, 1H), 4.34 (br s,2H), 4.00 (br s, 11.1), 3.86 (br s, 1H), 3.71-3.66 (m, 1H), 3.42 (br s,2H), 2.36 (d, 2H), 2.00 (s, 1H), 1.75-1.65 (m, 1H), 0.91 (d, 6H). MS(EI) for C₂₀H₂₁F₃IN₃O: 504 (MH⁺).

Example 12(f)

N-(cyclopropylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine:¹H NMR (400 MHz, CDCl₃): 8.48 (s, 1H), 7.39 (d, 1H), 7.32 (d, 1H),7.13-7.09 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 5.78 (s, 3H),4.36 (br s, 2H), 4.10 (br s, 1H), 3.94 (br s, 1H), 3.81-3.75 (m, 1H),2.49 (d, 2H), 2.01 (s, 4H), 0.94-0.86 (m, 1H), 0.53 (d, 2H), 0.13 (d,2H). MS (EI) for C₂₀H₁₉F₃IN₃O: 502 (MH⁺).

Example 12(g)

N-(cyclohexylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine:¹H NMR (400 MHz, CDCl₃): 8.48 (s, 1H), 7.38 (dd, 1H), 7.31 (d, 1H),7.13-7.08 (m, 1H), 6.83-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.55 (br s,2H), 4.33 (br m, 2H), 4.02 (br s, 1H) 3.87 (br s, 1H), 3.71-3.65 (m,1H), 2.38 (d, 2H), 1.74-1.68 (m, 4H), 1.46-1.36 (m, 1H), 1.27-1.12 (m,3H), 0.94-0.84 (m, 2H). MS (EI) for C₂₃H₂₅F₃IN₃O: 544 (MH⁺).

Example 12(h)

N-(cyclopentylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine:¹H NMR (400 MHz, CDCl₃): 8.32 (s, 1H), 7.37 (d, 1H), 7.31 (d, 1H),7.11-7.07 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.44-4.37 (m,3H), 4.02-3.96 (m, 1H), 2.84 (d, 2H), 2.54 (br s, 5H), 2.20-2.12 (m,1H), 1.88-1.81 (m, 2H), 1.68-1.54 (m, 4H), 1.24-1.15 (m, 2H). MS (11)for C₂₂H₂₃F₃IN₃O: 530 (MH⁺).

Example 131-({2,4-difluoro-6-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine

2,4,6-Trifluorobenzoic acid (643 mg, 3.65 mmol) and2-fluoro-4-iodoaniline (1.0 g, 4.22 mmol) were taken into acetonitrile(30 mL) followed by addition of lithium amide (290 mg, 12.7 mmol) andthe mixture was heated to 60° C. under a nitrogen atmosphere for onehour. On cooling to room temperature the mixture was added to 1 Naqueous hydrochloric acid (100 mL) and the precipitate formed wascollected by filtration and washed once with water then hexanes anddried in vacuo to give2,4-difluoro-6-[(2-fluoro-4-iodophenyl)amino]benzoic acid (849 mg, 59%yield) as a tan solid. ¹H-NMR (400 MHz, D₆-DMSO): 13.72 (br s, 1H), 9.46(s, 1H), 7.75 (d, 1H), 7.56 (d, 1H) 7.28 (tr, 1H), 6.73-6.67 (m, 1H),6.53 (d, 1H).

2,4-Difluoro-6-[(2-fluoro-4-iodophenyl)amino]benzoic acid (100 mg, 0.25mmol) was taken into DMF (1 mL) followed by addition of PyBOP (137 mg,0.26 mmol) and the mixture was stirred for 15 minutes then NMM (60 μL,0.5 mmol) and commercially available 1,1-dimethylethylazetidin-3-ylcarbamate (43 mg, 0.25 mmol) were subsequently added. Themixture was allowed to stir for 12 hours at room temperature thenpartitioned with ethyl acetate and water. The organic phase was washedthree times with additional water then brine and dried over anhydroussodium sulfate. Filtration and concentration followed by silica gelflash chromatography of the residue using hexanes:ethyl acetate 3:1 aseluent afforded 1,1-dimethylethyl[1-({2,4-difluoro-6-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate(125 mg) as a colorless oil.

The oil was taken into trifluoroacetic acid (1 mL) and allowed to standat room temperature for 5 minutes then concentrated in vacuo. Theresidue was portioned with ethyl acetate and saturated aqueous sodiumbicarbonate and the organic phase washed with brine then dried overanhydrous sodium sulfate. The organic solution was filtered andconcentrated then the residue taken into methanol (1 mL) followed byaddition of 4 N HCl in dioxane until the solution was acidic. Thesolution was concentrated and the residue triturated with ethyl ether togive a thick precipitate. The solid was collected by filtration anddried in vacuo to give1-({2,4-difluoro-6-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-aminehydrochloride (58 mg, 48% overall yield). ¹H-NMR (400 MHz, D₆-DMSO):8.67 (br s, 3H), 8.45 (s, 1H), 7.71 (d, 1H), 7.54 (d, 1H), 7.25 (tr,1H), 6.77 (tr, 1H), 6.48 (d, 1H), 4.28-4.23 (m, 2H), 4.13-4.06 (m, 3H).MS (EI) for C₁₆H₁₃F₃IN₃O: 448 (MH⁺).

Example 141-({4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine

2,4,5-Trifluorobenzoic acid (643 mg, 3.65 mmol) and2-fluoro-4-iodoaniline (1.0 g, 4.22 mmol) were taken into acetonitrile(30 mL) followed by addition of lithium amide (290 mg, 12.7 mmol) andthe mixture was heated to 60° C. under a nitrogen atmosphere for onehour. On cooling to room temperature the mixture was added to 1 Naqueous hydrochloric acid (100 mL) and the precipitate formed wascollected by filtration and washed once with water then hexanes anddried in vacuo to give4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (624 mg, 43%yield) as a tan solid. ¹H-NMR (400 MHz, D₆-DMSO): 13.65 (br s, 1H), 9.63(s, 1H), 7.84 (tr, 1H), 7.71 (d, 1H), 7.52 (d, 1H), 7.32 (tr, 1H),7.03-6.98 (dd, 1H).

4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (100 mg, 0.25mmol) was taken into DMF (1 mL) followed by addition of PyBOP (137-mg,0.26 mmol) and the mixture was stirred for 15 minutes then NMM (60 μL,0.5 mmol) and commercially available 1,1-dimethylethylazetidin-3-ylcarbamate (43 mg, 0.25 mmol) were subsequently added. Themixture was allowed to stir for 12 hours at room temperature thenpartitioned with ethyl acetate and water. The organic phase was washedthree times with additional water then brine and dried over anhydroussodium sulfate. Filtration and concentration followed by silica gelflash chromatography of the residue using hexanes:ethyl acetate 3:1 aseluent afforded 1,1-dimethylethyl[1-({4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate(131 mg) as a colorless oil. The oil was taken into trifluoroacetic acid(1 mL) and allowed to stand at room temperature for 5 minutes thenconcentrated in vacuo. The residue was portioned with ethyl acetate andsaturated aqueous sodium bicarbonate and the organic phase washed withbrine then dried over anhydrous sodium sulfate. The organic solution wasfiltered and concentrated then the residue taken into methanol (1 mL)followed by addition of 4 N HCl in dioxane until the solution wasacidic. The solution was concentrated and the residue triturated withethyl ether to give a thick precipitate. The solid was collected byfiltration and dried in vacuo to give1-({4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-aminehydrochloride (67 mg, 55% overall yield). ¹H-NMR (400 MHz, D₆-DMSO):9.02 (s, 1H), 8.54 (br s, 3H), 7.68 (dd, 1H), 7.53-7.47 (m, 2H), 7.22(tr, 1H), 7.16 (dd, 1H), 4.60 (br s, 1H), 4.23 (br s, 2H), 4.03 (br m,2H). MS (EI) for C₁₆H₁₃F₃IN₃O: 448 (MH⁺).

Example 15

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2,3-dihydroxypropyl)-3-hydroxyazetidine-3-carboxamide

1-(Diphenylmethyl)azetidin-3-ol hydrochloride (2.75 g, 9.98 mmol),prepared using procedures similar to those described for Scheme 1 of theGeneral Synthetic Section, 3 Å molecular sieves and 4-methylmorpholine(1.1 mL, 10.0 mmol) were suspended in dichloromethane (20 mL) at 0° C.4-Methylmorpholine N-oxide (2.93 g, 25.0 mmol) and tetrapropylammoniumperruthenate (140 mg, 0.399 mmol) were added and the mixture was stirredat ambient for 24 h. The mixture was filtered through a plug of silicausing 5% triethylamine in ethyl acetate as eluent. The filtrate wasconcentrated in vacuo and the residue was partitioned between ethylacetate and saturated sodium bicarbonate solution. The organic portionwas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. Column chromatography (silica gel, 8:1hexanes:ethyl acetate) gave 1-(diphenylmethyl)azetidin-3-one (871 mg,3.68 mmol, 37% yield): ¹H NMR (400 MHz, CDCl₃): 7.50-7.46 (m, 4H),7.33-7.27 (m, 4H), 7.27-7.19 (m, 2H), 4.59 (s, 1H), 4.01 (s, 4H); MS(EI) for C₁₆H₁₅NO: 238 (MH⁺).

1-(Diphenylmethyl)azetidin-3-one (600 mg, 2.53 mmol), was dissolved indichloromethane (1 mL) and treated with triethylamine (0.5 mL, 3.59mmol) and trimethylsilylcyanide (0.8 mL, 6.01 mmol) at ambient for 2 hand then the mixture was concentrated in vacuo to afford1-(diphenylmethyl)-3-[(trimethylsilyl)oxy]azetidine-3-carbonitrile (774mg, 2.30 mmol, 91% yield) as a yellow solid.1-(diphenylmethyl)-3-[(trimethylsilyl)oxy]azetidine-3-carbonitrile (250mg, 0.744 mmol) was dissolved m dichloromethane (2 mL) at 0° C. andconcentrated sulfuric acid (0.2 mL) was added dropwise. The mixture wasstirred at ambient for 2 h and then was cooled to 0° C. and 25% ammoniumhydroxide solution was added carefully dropwise to pH˜10-11. The mixturewas extracted twice with dichloromethane. The combined organic portionwas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to afford a residue which was triturated withhexanes/ether to afford1-(diphenylmethyl)-3-hydroxyazetidine-3-carboxamide (160 mg, 0.567 mmol,76% yield) as an off-white solid: ¹H NMR (400 MHz, CDCl₃): 7.92 (br s,1H), 7.39-7.34 (m, 4H), 7.33-7.27 (m, 4H), 7.27-7.19 (m, 2H), 5.61 (brs, 1H), 4.45 (s, 1H), 4.34 (s, 1H), 3.50 (dd, 2H), 3.20 (dd, 2H); MS(EI) for C₁₇H₁₈N₂O₂: 283 (MH⁺).

1-(Diphenylmethyl)-3-hydroxyazetidine-3-carboxamide (1.1 g, 3.90 mmol)was treated with 10% sodium hydroxide in ethanol (15 mL) and water (2mL) at reflux for 2 h and then was concentrated in vacuo. The residuewas neutralized with 1 N hydrochloric acid (pH˜7) and the precipitatewas collected by filtration and lyophilized to afford1-(diphenylmethyl)-3-hydroxyazetidine-3-carboxylic acid (assume 3.90mmol) which was used without further purification: ¹H NMR (400 MHz,d₆-DMSO): 7.45-7.40 (m, 4H), 7.31-7.25 (m, 4H), 7.21-7.15 (m, 2H), 4.52(s, 1H), 3.46 (dd, 2H), 3.02 (dd, 2H); MS (EI) for C₁₇H₁₇NO₃: 284 (MH⁺).

1-(Diphenylmethyl)-3-hydroxyazetidine-3-carboxylic acid (assume 3.90mmol) was suspended in methanol (40 mL) and 4 N hydrochloric acid indioxane (1 mL, 4 mmol) was added. 20 wt % Palladium hydroxide on carbon(100 mg) was added to the solution and the mixture was treated withhydrogen at 40 psi for 2 h. The mixture was filtered and the filtratewas concentrated in vacuo to afford 3-hydroxyazetidine-3-carboxylic acidhydrochloride which was dissolved in tetrahydrofuran (5 mL) and water (5mL) and treated with potassium carbonate (1.615 g, 11.7 mmol) anddi-tert-butyl dicarbonate (935 mg, 4.29 mmol) were added. The mixturewas stirred at ambient for 17 h and then the mixture was partitionedbetween ethyl acetate and water. The aqueous portion was extracted withethyl acetate and then was acidified to pH˜3-4 and extracted twice morewith ethyl acetate. The combined organic portion was washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuoto afford1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-hydroxyazetidine-3-carboxylicacid which was dissolved in DMF (3 mL).Benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate(2.028 g, 3.90 mmol) and N,N-diisopropylethylamine (0.7 mL, 4.03 mmol)were added. The mixture was stirred at ambient for 5 minutes and thenallylamine (0.6 mL, 8.03 mmol) was added and the mixture was stirred for17 h. The mixture was partitioned between ethyl acetate and 5% lithiumchloride. The organic portion was washed with 20% citric acid, saturatedsodium bicarbonate and brine, then was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. Column chromatography(silica gel, ethyl acetate) gave 1,1-dimethylethyl3-hydroxy-3-[(prop-2-en-1-ylamino)carbonyl]azetidine-1-carboxylate (782mg, 3.05 mmol, 78% yield from1-(diphenylmethyl)-3-hydroxyazetidine-3-carboxamide). 1,1-Dimethylethyl3-hydroxy-3-[(prop-2-en-1-ylamino)carbonyl]azetidine-1-carboxylate (782mg, 3.05 mmol) was dissolved in methanol (10 mL) and 4 N hydrochloricacid in dioxane (2 mL, 8 mmol) was added. The mixture was refluxed for15 minutes and then was concentrated in vacuo to afford3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide hydrochloride (3.05mmol).

3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (1.20 g, 3.05mmol), prepared using procedures similar to those described in U.S. Pat.No. 7,019,033, 4-(dimethylamino)pyridine (1.20 g, 9.86 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (701 mg,3.66 mmol) were dissolved in DMF (10 mL). The mixture was stirred atambient for 5 minutes and then3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide hydrochloride (3.05mmol) in DMF (5 mL) was added and the mixture was stirred for 15 h. Themixture was partitioned between ethyl acetate and 5% lithium chloride.The organic portion was washed with 20% citric acid, saturated sodiumbicarbonate and brine, then was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. Column chromatography (silica gel,60-85% ethyl acetate in hexanes) and then reverse phase HPLC gave1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide(150 mg, 0.282 mmol, 9% yield): ¹H NMR (400 MHz, d₆-DMSO): 8.64 (br s,1H), 8.13 (t, 1H), 7.58 (dd, 1H), 7.38 (dd, 1H), 7.34-7.28 (m, 1H),7.21-7.12 (m, 1H), 6.84 (br s, 1H), 6.72 (ddd, 1H), 5.83-5.72 (m, 1H),5.10-4.99 (m, 2H), 4.38 (d, 1H), 4.20 (d, 1H), 4.02 (d, 1H), 3.86 (d,1H), 3.73-3.68 (m, 2H); MS (EI) for C₂₀H₁₇F₃IN₃O₃: 532 (MH⁺).

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide(88 mg, 0.166 mmol) and 4-methylmorpholine N-oxide (58 mg, 0.496 mmol)were dissolved in acetone/water (4:1; 10 mL) and osmium tetroxide (2.5wt. % in water; 0.1 mL) was added. The solution was stirred at ambientfor 15 h, then was quenched with saturated sodium bisulfite (2 mL) andconcentrated in vacuo. The residue was partitioned between ethyl acetateand brine. The aqueous portion was extracted with ethyl acetate. Thecombined organic portion was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. Purification byreverse phase HPLC gave1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2,3-dihydroxypropyl)-3-hydroxyazetidine-3-carboxamide(68 mg, 0.120 mmol, 72% yield): ¹H NMR (400 MHz, d₆-DMSO): 8.65 (br s,1H), 7.72 (t, 1H), 7.58 (dd, 1H), 7.41-7.36 (m, 1H), 7.34-7.28 (m, 1H),7.21-7.12 (m, 1H), 6.92 (br s, 1H), 6.72 (ddd, 1H), 5.00-4.10 (br, 2H),5.10-4.99 (m, 2H), 4.39 (d, 1H), 4.20 (d, 1H), 4.02 (d, 1H), 3.54-3.45(m, 1H), 3.34-3.21 (m, 2H), 3.06-2.96 (m, 1H); MS (EI) forC₂₀H₁₉F₃IN₃O₅: 566 (MH⁺).

Example 15(a)

Using the same or analogous synthetic techniques and substituting, asnecessary, with alternative reagents, the following compounds of theinvention were prepared:1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidine-3-carboxamide:¹H NMR (400 MHz, d₆-DMSO): 8.63 (br s, 1H), 7.58 (dd, 1H), 7.42-7.36 (m,3H), 7.34-7.28 (m, 1H), 7.22-7.12 (m, 1H), 6.76-6.68 (m, 2H), 4.39 (d,1H), 4.19 (d, 1H), 4.00 (d, 1H), 3.83 (d, 1H); MS (EI) forC₁₇H₁₃F₃IN₃O₃: 492 (MH⁺).

Example 166-{[3-(aminomethyl)-3-(methyloxy)azetidin-1-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline

Phenylmethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (165 mg, 0.75mmol), prepared using procedures similar to those described in Reference3, in THF (I mL) was added to anhydrous ammonia saturated in THF (10 mL)and the mixture was allowed to stir in a sealed vessel at roomtemperature over 24 hours. The solution was then concentrated and takenback into THF (1 mL) followed by addition of di-tert-butyldicarbonate(164 mg, 0.75 mmol) and stirred for one hour at room temperature. Themixture was then concentrated and the residue purified by silica gelflash chromatography using hexanes:ethyl acetate (1:1) as eluent to givephenylmethyl3-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3-hydroxyazetidine-1-carboxylate(16.5 mg, 7% yield) and unreacted epoxide (120 mg, 73% recovery). ¹H-NMR(400 MHz, CDCl₃): 7.34 (m, 5H), 5.10 (br, 1H), 5.09 (s, 2H), 4.68 (s,1H), 3.90 (dd AB, 4H), 3.41 (d, 2H), 1.44 (s, 9H).

Phenylmethyl3-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3-hydroxyazetidine-1-carboxylate(16.5 mg, 0.05 mmol) and 10% Pd/C (8 mg) were taken into methanol (2 mL)and hydrogenated at ambient pressure over 12 hours. The catalyst wasremoved by filtration and the filtrate concentrated and dried in vacuo.The residue was taken into THF (1 mL) followed by addition of DIPEA (10μL, 0.06 mmol) and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoylfluoride (19.8 mg, 0.05 mmol), prepared using procedures similar tothose described in Reference 1, and the solution was stirred at roomtemperature for 30 minutes. Concentration and purification of theresidue by silica gel flash chromatography using hexanes:ethyl acetate(1:1.5) afforded 1,1-dimethylethyl{[1-({3,4-difluoro-2[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidine-3-yl]methyl}carbamate(19 mg, 66% yield).

1,1-Dimethylethyl{[1-({3,4-difluoro-2[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidine-3-yl]methyl}carbamate(8.0 mg, 0.014 mmol) and silver (1) oxide (12 mg, 0.05 mmol) were takeninto methyl iodide (0.5 mL) and the mixture was brought to reflux for 4hours. The suspension was then cooled to room temperature and dilutedwith an excess of ethyl ether then filtered. The filtrate wasconcentrated and purified by silica gel flash chromatography usinghexanes:ethyl acetate (1:1) as eluent to give 1,1-dimethylethyl{[1-({3,4-difluoro-2[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(methyloxy)azetidine-3-yl]methyl}carbamate(2 mg). The material was taken into TFA (0.5 mL) and allowed to standfor 5 minutes then concentrated in vacuo. The residue was azetropedtwice from methanol (2 mL) and the residue dried in vacuo to afford6-{[3-(aminomethyl)-3-(methyloxy)azetidin-1-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4-iodophenyl)anilinetrifluoroacetate salt (2.3 mg, 27% yield) as an amorphous solid. MS (EI)for C₁₈H₁₇F₃IN₃O: 492 (MH⁺).

Example 17

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{2-[(1-methylethyl)amino]ethyl}azetidin-3-ol

A solution of tert-butyl acetate (566 μL, 4.2 mmol) in THF (10 mL) wascooled to −78° C. To the solution was added LHMDS (5.25 mL of a 1.0 Msolution in hexanes, 5.25 mmol), and the resulting mixture was stirredfor 20 min at −78° C. To the solution was added1-(diphenylmethyl)azetidin-3-one (500 mg, 2.1 mmol), prepared usingprocedures similar to those described in Example 15. After stirring for1 h, saturated aqueous ammonium chloride was added, and the mixture waswarmed to rt. Water and ether were added, and the resulting biphasicmixture was partitioned. The aqueous phase was extracted once withether. The combined organic extracts were dried over magnesium sulfate,filtered, and concentrated in vacuo. The residue was purified by flashchromatography (80% hexanes: 20% ethyl acetate) to provide1,1-dimethylethyl [1-(diphenylmethyl)-3-hydroxyazetidin-3-yl]acetate asa pale yellow solid (644 mg, 1.8 mmol, 87% yield). ¹H NMR (400 MHz,CDCl₃): δ 7.40 (m, 4H), 7.26 (m, 4H), 7.19 (m, 2H), 4.40 (s, 1H), 4.02(s, 1H), 3.15 (m, 2H), 3.05 (m, 2H), 2.83 (s, 2H), 1.45 (s, 9H).

To a solution of 1,1-dimethylethyl[1-(diphenylmethyl)-3-hydroxyazetidin-3-yl]acetate (333 mg, 0.94 mmol)in THF (3 mL) at 0° C. was added lithium aluminum hydride (940 μL of a1.0 M solution in THF, 0.94 mmol). The mixture was stirred for 3 h 20min while warming to rt. Water (36 μL) was added carefully to thesolution, followed by 15% sodium hydroxide (36 μL) and more water (108μL). The resulting precipitate was removed by filtration through celite,and the filtrate was concentrated to dryness yielding1-(diphenylmethyl)-3-(2-hydroxyethyl)azetidin-3-ol (228 mg, 0.80 mmol,85% yield) as a colorless syrup. ¹H NMR (400 MHz, CDCl₃): δ 7.38 (m,4H), 7.26 (m, 4H), 7.19 (m, 2H), 4.37 (s, 1H), 3.92 (m, 2H), 3.32 (m,2H), 2.96 (m, 2H), 2.07 (m, 2H).

Palladium hydroxide (100 mg) was suspended in a solution of1-(diphenylmethyl)-3-(2-hydroxyethyl)azetidin-3-ol (228 mg, 0.80 mmol)in methanol (15 mL), and the mixture was subjected to an atmosphere ofhydrogen at 50 psi for 4 h. The catalyst was then removed by filtrationthrough celite, and the filtrate was concentrated in vacuo to provide3-(2-hydroxyethyl)azetidin-3-ol. This material was used in thesubsequent reaction without purification. To a solution of3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (314 mg, 0.80mmol), prepared using procedures similar to those described in U.S. Pat.No. 7,019,033, in DMF (4 mL,) was added PyBOP (416 mg, 0.80 mmol) andtriethylamine (223 μL, 1.6 mmol). Finally, the unpurified3-(2-hydroxyethyl)azetidin-3-ol was added, and the resulting mixture wasstirred at rt for 16 h. Water and ethyl acetate were added, and thelayers were separated. The aqueous phase was extracted with once morewith ethyl acetate. The combined organic extracts were washed withbrine, dried over magnesium sulfate, filtered, and concentrated invacuo. The residue was purified by flash chromatography, eluting withethyl acetate, to provide1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-hydroxyethyl)azetidin-3-olas a colorless oil (303 mg, 0.62 mmol, 78% yield). ¹H NMR (400 MHz,CDCl₃): δ 8.46 (s, 1H), 7.39 (dd, 1H), 7.32 (m, 1H), 7.13 (m, 1H), 6.81(m, 1H), 6.60 (m, 1H), 4.37 (br s, 1H), 4.28 (br m, 4H), 3.94 (br s,2H), 2.19 (br s, 1H), 2.02 (m, 2H); MS (EI) for C₁₈H₁₆F₃IN₂O₃: 491(M-H).

A solution of oxalyl chloride (13 μL, 0.15 mmol) in dichloromethane (1mL) was cooled to −78° C., and DMSO (22 μL, 0.31 mmol) was then added.To this mixture was added1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-hydroxyethyl)azetidin-3-ol(67.8 mg, 0.14 mmol) as a suspension in dichloromethane (1 mL). Afterstirring at −78° C. for 10 min, triethylamine (78 μL, 0.56 mmol) wasadded and the mixture was allowed to warm to rt. The solution wasdiluted with dichloromethane, and washed with 0.5 HCl. The aqueous phasewash then extracted with dichloromethane. The organic extracts werecombined, dried over magnesium sulfate, filtered, and concentrated. Theresidue was purified by flash chromatography to provide[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]acetaldehydeas a white solid (22.1 mg, 0.045 mmol, 32% yield). ¹H NMR (400 MHz,CDCl₃): δ 9.82 (s, 1H), 8.46 (s, 1H), 7.39 (m, 1H), 7.33 (m, 1H), 7.11(m, 1H), 6.81 (m, 1H), 6.61 (m, 1H), 4.32-3.96 (br m, 4H), 3.41 (t, 2H),3.07 (s, 1H); MS (EI) for C₁₈H₁₄F₃IN₂O₃: 491 (MH⁺).

To a solution of[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]acetaldehyde (38.0 mg, 0.078 mmol) in 1,2-dichloroethane (1 mL) wasadded isopropylamine (27 μL, 0.31 mmol) followed by sodiumtriacetoxyborohydride (26 mg, 0.12 mmol). The mixture was stirred for 3h before quenching with 1 drop of concentrated HCl. The quenched mixturewas concentrated to dryness, and then purified by preparative HPLC toprovide1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{2-[(1-methylethyl)amino]ethyl}azetidin-3-ol(21.5 mg) as a pale yellow solid. ¹H NMR (400 MHz, d₆-DMSO): δ 8.54 (s,1H), 7.57 (dd, 1H), 7.38 (dd, 1H), 7.31 (m, 1H), 7.17 (m, 1H), 6.67 (m,1H), 4.02 (m, 1H), 3.89 (m, 2H), 3.71 (m, 1H), 2.70 (m, 1H), 2.63 (m,2H), 1.86 (s, 3H), 1.75 (m, 2H), 0.97 (d, 6H); MS (EI) forC₂₁H₂₃F₃IN₃O₂: 534 (MH⁺).

Example 181-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{1,1-dimethyl-2-[(1-methylethyl)amino]ethyl}azetidin-3-ol

To a solution of1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one(500 mg, 1.12 mmol), prepared using procedures similar to thosedescribed in Example 6, in dichloromethane (5 mL) cooled to 0° C. wasadded titanium tetrachloride (125 μL, 1.12 mmol). The dark brownsolution was stirred at 0° C. for 45 minutes, followed by the additionof methyltrimethylsilyl dimethylketene acetal (550 μL, 2.24 mmol) at 0°C. Upon addition the solution was allowed to warm to room temperature,and was stirred for 1 hour. The reaction mixture was then partitionedbetween saturated aqueous sodium bicarbonate and ethyl acetate. Theaqueous portion was extracted twice using ethyl acetate. The combinedorganic portion was washed with water, brine, dried over sodium sulfate,filtered and concentrated in vacuo to afford a brown oil which waspurified by column chromatography. Eluting with 10% diethyl ether indichloromethane, the isolated product was concentrated in vacuo toafford 520 mg, 0.95 mmol (85%) of methyl2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-methylpropanoateas a white foam. ¹H NMR (400 MHz, CDCl₃): 8.34 (s, 1H), 7.38 (d, 1H),7.31 (d, 1H), 7.13-7.08 (m, 1H), 6.85-6.77 (m, 1H), 6.63-6.56 (m, 1H),4.26-4.20 (m, 2H), 4.13-4.09 (m, 1H), 4.00-3.93 (m, 1H), 3.70 (s, 3H),1.23 (s, 6H). MS (EI) for C₂₁H₂₀F₃IN₂O₄: 547 (MH⁺).

A solution of methyl2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-methylpropanoate(520 mg, 0.95 mmol) in 4N aqueous potassium hydroxide (5 mL) was stirredat 50° C. for 1 hour. Using concentrated aqueous hydrochloric acid, thereaction mixture was acidified to pH 5, and then partitioned with ethylacetate. The aqueous portion was extracted twice using ethyl acetate,and the combined organic portion was washed with brine, dried oversodium sulfate, filtered and concentrated in vacuo to afford 300 mg,0.56 mmol (59%) of2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-methylpropanoicacid as a white solid. ¹H NMR (400 MHz, DMSO): 8.49 (s, 1H), 7.57-7.52(m, 1H), 7.37-7.25 (m, 2H), 7.17-7.13 (m, 1H), 6.68-6.58 (m, 1H),3.98-3.94 (m, 2H), 3.80-3.77 (m, 1H), 3.55-3.52 (m, 1H), 0.88 (s, 6H).MS (EI) for C₂₀H₁₈F₃IN₂O₄: 535 (MH⁺).

To solution of2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-methylpropanoicacid (300 mg, 0.56 mmol) in tetrahydrofuran (5 mL) was addedtriethylamine (80 μL, 0.56 mmol), followed by PyBOP (295 mg, 0.56 mmol)and finally sodium borohydride (64 mg, 1.68 mmol). The mixture wasstirred at room temperature for 1 hour. The reaction mixture wasquenched by adding 20% aqueous citric acid, and then partitioned withethyl acetate. The organic portion was washed with saturated aqueoussodium bicarbonate, brine, dried over sodium sulfate, filtered andconcentrated in vacuo to afford a white solid which was purified bycolumn chromatography. Eluting with 60% ethyl acetate in hexanes, theisolated product was concentrated in vacuo to afford 238 mg, 0.46 mmol(82%) of1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-hydroxy-1,1-dimethylethyl)azetidin-3-olas a white solid. ¹H NMR (400 MHz, DMSO): 8.53 (s, 1H), 7.57 (d, 1H),7.38-7.28 (m, 2H), 7.22-7.15 (m, 1H), 6.70-6.64 (m, 1H), 5.61 (s, 1H),4.57 (br s, 1H), 4.30-4.27 (m, 1H), 4.18-4.15 (m, 1H), 3.80-3.77 (m,1H), 3.68-3.64 (m, 1H), 3.25 (s, 2H), 0.76 (d, 6H); MS (EI) forC₂₀H₂₀F₃IN₂O₃: 521 (MH⁺).

A mixture of1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-hydroxy-1,1-dimethylethyl)azetidin-3-ol(200 mg, 0.38 mmol) and Dess-Martin periodinane (240 mg, 0.57 mmol) indichloromethane (2 mL) was stirred at room temperature for 2 hours. 10%aqueous sodium thiosulfate (2 mL), and saturated aqueous sodiumbicarbonate (2 mL) was added and the mixture was stirred at roomtemperature for 15 minute. The mixture was partitioned and the aqueouslayer was extracted twice using dichloromethane. The combined organicportion was washed with brine, dried over sodium sulfate, filtered andconcentrated in vacuo, to afford a white solid which was purified bycolumn chromatography. Eluting with 30% ethyl acetate in hexanes, theisolated product was concentrated in vacuo to afford 100 mg, 0.20 mmol(53%) of2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-methylpropanalas a white solid, which was immediately dissolved in tetrahydrofuran (2mL). To the solution was added isopropylamine (34 μL, 0.40 mmol),followed by triacetoxyborohydride (212 mg, 1.0 mmol). The solution wasstirred at room temperature for 15 hours. The reaction mixture wasconcentrated in vacuo and partitioned between 20% aqueous citric acidand ethyl acetate. The aqueous portion was extracted twice using ethylacetate, and the combined organic portion was washed with saturatedaqueous sodium bicarbonate, brine, dried over sodium sulfate, filteredand concentrated in vacuo to afford a yellow oil which was purified bypreparative reverse phase HPLC. The isolated product was concentrated invacuo to afford 50 mg, 0.07 mmol (36%) of1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{1,1-dimethyl-2-[(1-methylethyl)amino]ethyl}azetidin-3-olacetate salt as a white solid. ¹H NMR (400 MHz, DMSO): 8.47 (br s, 1H),7.55 (d, 1H), 7.36-7.29 (m, 2H), 7.22-7.15 (m, 1H), 6.68-6.63 (m, 1H),4.17-4.08 (m, 2H), 3.76-3.73 (m, 1H), 3.56-3.52 (m, 1H), 2.58-2.51 (m,1H), 2.45-2.37 (m, 2H), 0.92 (t, 6H), 0.78 (d, 6H); MS (EI) forC₂₃H₂₇F₃IN₃O₂: 562 (MH⁺).

Example 191-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-methylethyl)amino]methyl}azetidin-3-amine

To a solution of the1-(diphenylmethyl)-3-[(phenylmethyl)amino]azetidine-3-carbonitrile (0.80g, 2.2 mmol), prepared using procedures similar to those described inKozikowski and Fauq Synlett 1991, 11, 783-4, in ethanol (30 mL) wasadded solid sodium hydroxide (7.5 mmol), and the resulting mixture wasstirred at room temperature for 3 days. Water (6 mL) was added to thereaction mixture and stirring was continued at 90° C. for 2 h. The pH ofthe reaction mixture was adjusted to 5 with concentrated hydrochloricacid and a white solid precipitated. The mixture was cooled, dilutedwith water (50 mL) and the solid was collected, washed with water thendried in vacuo to give the1-(diphenylmethyl)-3-[(phenylmethyl)amino]azetidine-3-carboxylic acid(0.75 g, 88% yield), MS (EI) for C₂₄H₂₄N₂O₂: 373 (MH⁺).

To a mixture of1-(diphenylmethyl)-3-[(phenylmethyl)amino]azetidine-3-carboxylic acid(0.50 g, 1.34 mmol), N,N-diisopropylethylamine (0.47 mL, 2.68 mmol) inDMF (3 mL) was added 1-benzotriazolyloxytripyrrolidinylphosphoniumhexafluorophosphate (1.34 g, 2.68 mol) and the resulting mixture wasstirred at room temperature for 10 minutes. To this mixture was added2-propylamine (0.22 mL, 2.68 mmol) and stirring was continued for 18 h.The reaction mixture was diluted with ethyl acetate (100 mL) and washedwith 2% aqueous citric acid, 5% lithium chloride, and brine solutions(50 mL each), dried over sodium sulfate, filtered and concentrated togive an oily residue which was purified by flash chromatography (silicagel, eluting with 15-25% ethyl acetate-hexane) to give1-(diphenylmethyl)-N-(1-methylethyl)-3-[(phenylmethyl)amino]azetidine-3-carboxamide(0.51 g, 92% yield), MS (EI) for C₂₇H₃₁N₃O: 414 (MH⁺).

To a solution of the1-(diphenylmethyl)-N-(1-methylethyl)-3-[(phenylmethyl)amino]azetidine-3-carboxamide(0.40 g, 0.97 mmol) in tetrahydrofuran (10 mL) at room was added asolution of lithium aluminum hydride in tetrahydrofuran (1M, 2.90 mL,2.90 mmol), and the resulting mixture was stirred at 50° C. for 3 h. Thereaction mixture was cooled to room temperature, quenched with 20%aqueous hydroxide solution (1 mL), diluted with ether (50 mL) andfiltered. The filtrate was washed with brine solution (20 mL each),dried over sodium sulfate, filtered and concentrated to give an oilyresidue which was purified by flash chromatography (silica gel, elutingwith 5% methanol-dichloromethane) to give1-(diphenylmethyl)-3-{[(1-methylethyl)amino]methyl}-N-(phenylmethyl)azetidin-3-amine(0.35 g, 90% yield), ¹H NMR (400 MHz, CDCl₃): 7.42-7.14 (m, 15H), 4.34(s, 1H), 3.66 (s, 2H), 3.22-3.18 (d, 2H), 2.97 (s, 2H), 2.90-2.86 (d,2H), 2.68-2.62 (p, 1H), 1.09-1.07 (d, 6H); MS (EI) for C₂₇H₃₃N₃: 400(MH⁺).

To a solution of the1-(diphenylmethyl)-3-{[(1-methylethyl)amino]methyl}-N-(phenylmethyl)azetidin-3-amine(0.35 g, 0.88 mmol) in methanol was added a solution of hydrogenchloride in dioxane (4 molar solution, 0.96 mL, 4.40 mmol) and theresulting mixture was concentrated to give a white solid which was takenback into methanol. To this solution were added palladium hydroxide (20%on carbon, 0.50 g, 0.19 mmol) and the resulting mixture shaken at 50 psiin a Parr apparatus for 3 h. The reaction mixture was filtered andconcentrated to give a solid, which was washed with ether and dried invacuo to give 3-{[(1-methylethyl)amino]methyl}azetidin-3-aminehydrochloride as a white solid (0.18 g, 81% yield). MS (EI) for C₇H₁₇N₃:144 (MH⁺).

To a mixture of the 3-{[(1-methylethyl)amino]methyl}azetidin-3-aminehydrochloride (20 mg, 0.079 mmol) in saturated sodium bicarbonatesolution (1.0 mL) and dioxane (1.0 mL) was added3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (31 mg,0.079 mmol), prepared using procedures similar to those described inReference 1, and the resulting mixture was stirred at room temperaturefor 18 h. The reaction mixture was diluted with water (5 mL) andextracted with ethyl acetate (3×5 mL). The combined extract was washedwith water then brine solution (5 mL each), dried over sodium sulfate,filtered and concentrated to give an oily residue which was purified byreverse phase HPLC to afford1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-methylethyl)amino]methyl}azetidin-3-amine(15 mg, 37% yield). ¹H NMR (400 MHz, d₄-Methanol): 7.46-7.43 (dd, 1H),7.35-7.33 (dd, 1H), 7.31-7.27 (m, 1H), 7.08-7.01 (dd, 1H), 6.63, 6.58(td, 1H), 4.09-4.07 (d, 1H), 3.91-3.85 (dd, 2H), 3.76-3.73 (d, 1H),2.80-2.74 (m, 1H), 2.73 (s, 2H), 1.07-1.05 (d, 6H); MS (EI) forC₂₀H₂₂F₃IN₄O: 519 (MH⁺).

Example 203-(1-amino-2-methylpropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol

1,1-Dimethylethyl 3-oxoazetidine-1-carboxylate (677.2 mg, 3.96 mmol),prepared using procedures similar to those described in Example 3, wastaken into 2-methyl-1-ntropropane (5 mL) then cooled to 0° C. followedby addition of potassium tert-butoxide (444 mg, 3.96 mmol) and theresulting mixture was allowed to warm to room temperature over 30minutes. The mixture was partitioned with ethyl acetate and 0.5 Naqueous hydrochloric acid then once with water and brine then dried overanhydrous magnesium sulfate. Filtration and concentration afforded aresidue (1.5 g) that was further purified by silica gel flashchromatography using 3:1 hexanes:ethyl acetate as eluent to give1,1-dimethylethyl3-hydroxy-3-(2-methyl-1-nitropropyl)azetidine-1-carboxylate (730 mg, 67%yield) as a colorless crystalline solid. ¹H-NMR (400 MHz, CDCl₃): 4.50(d, 1H), 3.93 (dd AB, 2H), 3.85 (s, 2H), 3.58 (s, 1H), 2.54-2.48 (m,1H), 1.44 (s, 9H), 1.04 (d, 6H).

1,1-Dimethylethyl3-hydroxy-3-(2-methyl-1-nitropropyl)azetidine-1-carboxylate (105 mg,0.38 mmol) was taken into methanol (1 mL) followed by addition of 4 Nanhydrous hydrogen chloride in dioxane (1 mL) and the acidic solutionwas allowed to stand for 15 minutes at room temperature thenconcentrated and dried in vacuo to an amorphous residue.3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (150 mg, 0.38mmol), prepared using procedures similar to those described in U.S. Pat.No. 7,019,033, was taken into DMF (0.7 mL) followed by addition of PyBOP(198 mg, 0.38 mmol) and the solution was allowed to stir for 10 minutesat room temperature. The above amine hydrochloride salt and DIPEA (190μL, 1.1 mmol) in DMF solution (0.7 mL) was added and the mixture wasallowed to stir for one hour at room temperature. The mixture waspartitioned with ethyl acetate and 0.5 N aqueous hydrochloric acid andthe organic phase washed three times with water then brine and driedover anhydrous magnesium sulfate. Filtration and concentration affordeda residue that was further purified by silica gel flash chromatographyusing 1.5:1 hexanes:ethyl acetate as eluent to give1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-methyl-1-nitropropyl)azetidin-3-ol(189 mg, 90% yield) as an amorphous solid. ¹H-NMR (400 MHz, CDCl₃): 8.41(br s, 1H), 7.41 (dd, 1H), 7.34 (d, 1H), 7.09 (br m, 1H), 6.81 (q, 1H),6.65-6.60 (m, 1H), 4.49 (d, 1H), 4.15-4.09 (m, 4H), 3.66 (s, 1H),2.56-2.46 (m, 1H) 1.03 (d, 6H).

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-methyl-1-nitropropyl)azetidin-3-ol(189 mg, 0.34 mmol) was taken into 4:1 THF:water (5 mL) followed byaddition of iron powder (192 mg, 3.4 mmol) and ammonium formate (429 mg,6.8 mmol) and the mixture was heated to reflux. After four hoursadditional aliquots of iron powder (192 mg, 3.4 mmol) and ammoniumformate (429 mg, 6.8 mmol) were added and the mixture was allowed toreflux an additional 12 hours. The mixture was cooled to roomtemperature and diluted with ethyl acetate then filtered. The filtratewas partitioned with ethyl acetate and saturated aqueous sodiumbicarbonate then the organic layer washed with brine and dried overanhydrous sodium sulfate. Filtration and concentration afforded aresidue that was further purified by silica gel flash chromatographyusing ethyl acetate to 10% methanol in dichloromethane as eluents togive a residue (36.5 mg) that was further purified by preparativereverse phase HPLC to give3-(l-amino-2-methylpropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-oltrifluoroacetate salt (7.9 mg) as a colorless amorphous solid afterlyophilization of the combined pure fractions. ¹H-NMR (400 MHz,D₆-DMSO): 8.63 (s, 1H), 7.58 (dd, 1H), 7.37 (d, 1H), 7.35-7.31 (m, 1H),7.17 (q, 1H), 6.71-6.66 (m, 1H), 4.23 (dd, 1H), 4.03 (dd, 1H), 3.80 (dd,1H), 3.66 (dd, 1H), 2.34 (dd, 1H), 1.79-1.70 (m, 1H), 0.84-0.77 (m, 6H).MS (EI) for C₂₀H₂₁F₃IN₃O₂: 520 (MH⁺).

Using the same or analogous synthetic techniques and substituting, asnecessary, with alternative reagents, the following compounds of theinvention were prepared:

Example 20(a)

3-(1-aminoethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.56 (s, 1H), 7.91 (br s, 2H), 7.58 (d, 1H),7.39 (d, 1H), 7.36-7.32 (m, 1H), 7.24-7.17 (m, 1H), 6.72-6.65 (m, 2H),4.33-4.29 (m, 1H), 4.23-4.19 (m, 1H), 4.16-4.14 (m, 1H), 4.07-3.94 (m,1H), 3.82-3.77 (m, 1H), 3.51-3.45 (m, 1H), 1.15-1.12 (m, 1H), 1.10-1.08(m, 1H). MS (EI) for C₁₈H₁₇F₃IN₃O₂: 492 (MH⁺).

Example 20(b)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[1-(ethylamino)ethyl]azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.61 (d, 1H), 8.50 (s, 1H), 8.20 (s, 1H),7.59 (d, 1H), 7.39 (d, 1H), 7.36-7.32 (m, 1H), 7.24-7.17 (m, 1H), 6.82(s, 1H), 6.74-6.67 (m, 1H), 4.38 (d, 1H), 4.27 (d, 1H), 4.18 (d, 1H),4.06 (d, 2H), 3.99 (d, 1H), 3.89 (d, 1H), 3.82 (d, 1H), 3.49-3.43 (m,1H), 3.04-2.80 (m, 4H), 1.21-1.12 (m, 6H). MS (EI) for C₂₀H₂₁F₃IN₃O₂:520 (MH⁺).

Example 20(c)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-nitroethyl)azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.57 (d, 1H), 7.58 (d, 1H), 7.38 (d, 1H),7.37-7.33 (m, 1H), 7.22-7.17 (m, 1H), 6.73-6.66 (m, 1H), 6.57 (s, 1H),5.06-4.97 (m, 1H), 4.54 (d, 0.5H), 4.37 (d, 0.5H), 4.29 (d, 0.5H), 4.14(d, 0.5H), 4.05 (d, 0.5H), 3.95 (d, 0.5H), 3.86 (d, 0.5H), 3.80 (d,0.5H), 1.44-1.38 (m, 3H). MS (EI) for C₁₈H₁₆F₃IN₃O₄: 523 (MH⁺).

Example 20(d)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[1-(methylamino)ethyl]azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.63-8.55 (m, 1H), 8.44-8.23 (m, 1H), 7.79(br s, 1H), 7.60 (d, 1H), 7.39 (d, 1H), 7.36-7.31 (m, 1H), 7.24-7.17 (m,1H), 6.82 (br s, 0.5H), 6.73-6.65 (m, 1H), 4.38-3.77 (m, 4H), 1.18-1.07(m, 3H). MS (EI) for C₁₉H₁₉F₃IN₃O₂: 505 (M⁺).

Example 20(c)

methyl{1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate:¹H NMR (400 MHz, d₆-DMSO): 8.59 (d, 1H), 7.58 (d, 1H), 7.41-7.05 (m,4H), 6.72-6.64 (m, 1H), 5.84 (d, 1H), 4.20 (d, 0.5H), 4.08-4.04 (m, 1H),3.92-3.85 (m, 1.5H), 3.76-3.71 (m, 1H), 3.69-3.63 (m, 1H), 3.46 (d, 2H),0.99-0.95 (m, 3H). MS (EI) for C₂₀H₁₉F₃IN₃O₄: 550 (MH⁺).

Example 20(f)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[1-(dimethylamino)ethyl]azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 9.45 (s, 1H), 8.61 (d, 1H), 7.60 (d, 1H),7.39 (d, 1H), 7.38-7.33 (m, 1H), 7.24-7.18 (m, 1H), 7.05 (s, 1H),6.73-6.66 (m, 1H), 4.48 (d, 0.5H), 4.36 (d, 0.5H), 4.26 (d, 0.5H),4.16-4.11 (m, 1H), 4.00-3.94 (m, 1H), 3.86 (d, 0.5H), 3.60-3.54 (m, 1H),2.75-2.70 (m, 3H), 2.66-2.62 (br s, 3H), 1.22 (dd, 3H). MS (EI) forC₂₀H₂₁F₃IN₃O₂: 520 (MH⁺).

Example 20(g)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-nitropropyl)azetidin-3-ol:¹H NMR (400 MHz, CD₃OD): 7.46 (m, 1H), 7.35 (m, 1H), 7.28 (m, 1H), 7.07(m, 1H), 6.61 (m, 1H), 4.65 (m, 1H), 4.44 (m, 1H), 4.25 (m, 1H), 4.02(m, 1H), 3.86 (m, 1H), 2.04 (m, 1H), 1.76 (m, 1H), 0.94 (m, 3H). MS (EI)for C₁₉H₁₇F₃IN₃O₄: 536 (MH⁺).

Example 20(h)

3-(1-aminopropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:¹H NMR (400 MHz, CD₃OD): 7.45 (m, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 7.05(m, 1H), 6.61 (m, 1H), 4.21 (m, 1H), 4.09-3.86 (m, 21-1). 3.78 (m, 1H),2.63 (m, 1H), 1.50 (m, 1H), 1.24 (m, 1H), 0.98 (m, 3H). MS (EI) forC₁₉H₁₉F₃IN₃O₂: 506 (MH⁺).

Example 20(i)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[1-(ethylamino)propyl]azetidin-3-ol:¹H NMR (400 MHz, CD₃OD): 7.45 (m, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 7.05(m, 1H), 6.61 (m, 1H), 4.23 (m, 1H), 4.02 (m, 1H), 3.90 (m, 1H), 3.79(m, 1H), 2.70 (m, 1H), 2.54 (m, 1H), 1.53 (m, 1H), 1.40 (m, 1H), 1.05(m, 3H), 0.95 (m, 3H). MS (EI) for C₂₁H₂₃F₃IN₃O₂: 534 (MH⁺).

Example 20(j)

3-[1-(diethylamino)propyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:¹H NMR (400 MHz, CD₃OD): 7.44 (m, 1H), 7.33 (m, 1H), 7.27 (m, 1H), 7.07(m, 1H), 6.60 (m, 1H), 4.21 (m, 1H), 4.10 (m, 1H), 4.03-3.70 (m, 2H),2.71-2.45 (m, 5H), 1.67 (m, 1H), 1.49 (m, 1H), 0.94 (m, 9H). MS (EI) forC₂₃H₂₇F₃IN₃O₂: 562 (MH⁺).

Example 20(k)

3-[amino(phenyl)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol):MS (EI) for C₂₃H₁₉F₃IN₃O₂: 554 (MH⁺).

Example 20(m)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(3-methyl-1-nitrobutyl)azetidin-3-ol):¹H NMR (400 MHz, CDCl₃): 8.38 (s, 1H), 7.39 (dd, Ill), 7.34-7.31 (m,1H), 7.14-7.10 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.58 (m, 1H), 4.68 (dd,1H), 4.23-4.04 (br m, 4H), 2.13 (t, 2H), 1.64-1.44 (br m, 3H), 0.93 (d,6H); MS (EI) for C₂₁H₂₁F₃IN₃O₄: 564 (MH⁺).

Example 20(n)

3-(1-aminobutyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.48-7.43 (d, 1H), 7.38-7.33 (d,1H), 7.32-7.26 (m, 1H), 7.09-7.00 (q, 1H), 6.66-6.58 (t, 1H), 4.33-4.22(d, 1H), 4.13-3.81 (m, 3H), 3.17-3.09 (t, 1H), 1.93-1.89 (s, 3H),1.89-1.82 (t, 3H), 1.56-1.24 (m, 4H), 0.97-0.88 (t, 3H); MS (EI) forC₂₀H₂₁F₃IN₃O₂: 520 (MH⁺).

Example 20(o)

3-(1-aminocyclopentyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CDCl₃): 8.27-8.21 (s, 1H), 7.42-7.36 (d,1H), 7.34-7.29 (d, 1H), 7.15-7.09 (t, 1H), 7.09-7.01 (q, 1H), 6.88-6.79(q, 1H), 6.63-6.53 (m, 1H), 4.18-3.92 (m, 4H), 2.12-2.08 (s, 3H),2.06-1.70 (m, 7H), 0.92-0.68 (m, 4H); MS (EI) for C₂₁H₂₁F₃IN₃O₂: 532(MH⁺).

Example 20(p)

N-{1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}acetamide:¹H NMR (400 MHz, CDCl3): 8.42 (s, 1H), 7.41-7.38 (dd, 1H), 7.34-7.32(dt, 1H), 7.12-7.09 (m, 1H), 6.85-6.78 (m, 1H), 6.63-6.57 (m, 1H), 5.76(b, 1H), 4.28-3.98 (m, 511H), 2.00 (s, 3H), 1.20-1.19 (d, 3H); MS (EI)for C₂₀H₁₉F₃IN₃O₃; 534 (MH⁺).

Example 20(q)

(2R)-N-{1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanamide:¹H NMR (400 MHz, CDCl₃): 8.47 (s, 1H), 7.45-7.40 (m, 5H), 7.33-7.31 (m,1H), 7.21-7.19 (m, 1H), 7.12-7.05 (m, 1H), 6.85-6.76 (m, 1H), 6.63-6.58(m, 1H), 4.20-3.99 (m, 5H), 3.36 (s, 1.5H), 3.34 (s, 1.5H), 1.27-1.25(d, 1.5H), 1.24-1.22 (d, 1.5H); MS (EI) for C₂₈H₂₄F₆IN₃O₄: 708 (MH⁺).

Example 20(r)

(2R)-N-{(1R)-1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanamide:¹H NMR (400 MHz, CDCl₃): 8.49 (s, 1H), 7.46-7.391 (m, 5H), 7.33-7.31 (m,1H), 7.21-7.16 (m, 1H), 7.14-7.10 (m, 1H), 6.85-6.79 (m, 1H), 6.64-6.58(m, 1H), 4.24-4.00 (m, 5H), 3.35 (s, 3H), 1.25-1.23 (d, 3H); MS (EI) forC₂₈H₂₄F₆IN₃O₄: 708 (MH⁺).

Example 20(s)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-methyl-1-nitroethyl)azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.28 (s, 1H), 7.41-7.38 (dd, 1H), 7.34-7.32(dt, 1H), 7.14-7.10 (m, 1H), 6.87-6.81 (m, 1H), 6.64-6.59 (m, 1H),4.33-4.15 (m, 4H), 1.64 (s, 6H); MS (EI) for C₁₉H₁₇F₃IN₃O₄: 536 (MH⁺).

Example 20(t)

3-(1-amino-1-methylethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:¹H NMR (400 MHz, CDCl3): 8.30 (s, 1H), 7.39-7.36 (dd, 1H), 7.32-7.30(dt, 1H), 7.13-7.09 (m, 1H), 6.85-6.79 (m, 1H), 6.62-6.56 (m, 1H),4.25-3.97 (m, 4H), 1.14 (s, 6H); MS (EI) for C₁₉H₁₉F₃IN₃O₂: 506 (MH⁺).

Example 21

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{1-[(trans-4-hydroxycyclohexyl)amino]ethyl}azetidin-3-olHydrochloride

Potassium tert-butoxide (1.672 g, 14.9 mmol) andethyltriphenylphosphonium bromide (5.538 g, 14.9 mmol) were stirred inether (30 mL) at ambient for 1 h. 1,1-Dimethylethyl3-oxoazetidine-1-carboxylate (954 mg, 6.0 mmol), prepared usingprocedures similar to those described in Example 3, was added and themixture was 35° C. for 4.5 h. Mixture was filtered through celite andthe solid was washed with ether. The filtrate was washed with water,brine, dried over anhydrous sodium sulfate, filtered and concentrated invacuo. Column chromatography (silica gel, 20% ether in hexanes) gave1,1-dimethylethyl 3-ethylideneazetidine-1-carboxylate (506 mg, 2.76mmol, 49% yield): ¹H NMR (400 MHz, CDCl₃): 5.37-5.28 (m, 1H), 4.47-4.39(m, 4H), 1.56-1.51 (m, 3H), 1.45 (s, 9H).

1,1-Dimethylethyl 3-ethylideneazetidine-1-carboxylate (506 mg, 2.76mmol), and 4-methylmorpholine N-oxide (1.04 g, 8.89 mmol) were dissolvedin acetone/water (4:1; 30 mL) and osmium tetroxide (2.5 wt. % ini-butanol; 0.2 mL) was added. The solution was stirred at ambient for 5days, then was quenched with saturated sodium bisulfite (2 mL) andconcentrated in vacuo. The residue was partitioned between ethyl acetateand brine. The aqueous portion was extracted with ethyl acetate. Thecombined organic portion was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. Columnchromatography (silica gel, ethyl acetate) gave 1,1-dimethylethyl3-hydroxy-3-(1-hydroxyethyl)azetidine-1-carboxylate (375 mg, 1.73 mmol,63% yield): ¹H NMR (400 MHz, CDCl₃): 4.00-3.77 (m, 5H), 2.65 (br s, 1H),1.86, (br s, 1H), 1.44 (s, 9H), 1.25 (d, 3H).

1,1-Dimethylethyl 3-hydroxy-3-(1-hydroxyethyl)azetidine-1-carboxylate(200 ag, 0.922 mmol) was dissolved in methanol (5 mL) and 4 Nhydrochloric acid in dioxane (1 mL, 4 mmol) was added. The mixture wasrefluxed for 15 minutes and then was concentrated in vacuo to afford3-(1-hydroxyethyl)azetidin-3-ol hydrochloride (0.922 mmol).

3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (362 mg, 0.921mmol), prepared using procedures similar to those described in U.S. Pat.No. 7,019,033, 4-(dimethylamino)pyridine (337 mg, 2.76 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (212 mg,1.11 mmol) were dissolved in DMF (3 mL). The mixture was stirred atambient for 5 minutes and then 3-(1-hydroxyethyl)azetidin-3-olhydrochloride (0.922 mmol) in DMF (2 mL) was added and the mixture wasstirred for 15 h. The mixture was partitioned between ethyl acetate and5% lithium chloride. The organic portion was washed with 20% citricacid, saturated sodium bicarbonate and brine, then was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Columnchromatography (silica gel, 80% ethyl acetate in hexanes) gave1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-hydroxyethyl)azetidin-3-ol(296 mg, 0.602 mmol, 65% yield): MS (EI) for C₁₈H₁₆F₃IN₂O₃: 493 (MH⁺).

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-hydroxyethyl)azetidin-3-ol(267 mg, 0.543 mmol), was dissolved in dichloromethane (10 mL) andtreated with 4-(dimethylamino)pyridine (80 mg, 0.661 mmol) and2,4,6-triisopropylbenzenesulfonyl chloride (183 mg, 0.604 mmol) atambient for 15 h. Triethylamine (0.076 mL, 0.545 mmol) was added and themixture was stirred at ambient for 3 h and then at 35° C. for 4 h andthen at ambient for a further 15 h. 2,4,6-Triisopropylbenzenesulfonylchloride (110 mg, 0.363 mmol) was added and the mixture was stirred at35° C. for 3 h and then 4-(dimethylamino)pyridine (80 mg, 0.661 mmol)was added and the mixture was stirred at 35° C. for 2 h.2,4,6-Triisopropylbenzenesulfonyl chloride (303 mg, 1.0 mmol) was addedand the mixture was stirred at 35° C. for a further 18 h. The mixturewas adsorbed on to silica and purified by column chromatography (silicagel, 30-50% ethyl acetate in hexanes) to give1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl2,4,6-tris(1-methylethyl)benzenesulfonate (201 mg, 0.265 mmol, 49%yield): MS (EI) for C₃₃H₃₈F₃IN₂O₅S: 759 (MH⁺).

1-[1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl2,4,6-tris(1-methylethyl)benzenesulfonate (194 mg, 0.256 mmol) wasdissolved in tetrahydrofuran (2 mL) and was cooled to 0° C. Sodiumhydride (60 wt % dispersion in oil; 31 mg, 0.775 mmol) was added and themixture was stirred at 0° C. for 15 minutes. The mixture was quenchedwith saturated sodium bicarbonate solution and partitioned with ethylacetate. The aqueous portion was extracted with ethyl acetate. Thecombined organic portion was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. Columnchromatography (silica gel, 50% ethyl acetate in hexanes) gave2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-[(2-methyl-1-oxa-5-azaspiro[2.3]hex-5-yl)carbonyl]aniline(120 mg, 0.253 mmol, 99% yield): MS (EI) for C₁₈H₁₄F₃IN₂O₂: 475 (MH⁺).

2,3-Difluoro-N-(2-fluoro-4-iodophenyl)-6-[(2-methyl-1-oxa-5-azaspiro[2.3]hex-5-yl)carbonyl]aniline(50 ag, 0.105 mmol) was dissolved in dimethylsulfoxide (0.8 mL) andtreated with trans-4-cyclohexanolamine (70 mg, 0.609 mmol) with 100 Wmicrowave power at 100° C. for 45 minutes. The mixture was purified byreverse phase HPLC and the clean fractions were combined, neutralizedwith saturated sodium bicarbonate solution and the organic solvent wasremoved in vacuo. The remaining aqueous residue was extracted twice withethyl acetate. The combined organic portion was washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated in vacuo togive a residue which was treated with aqueous hydrochloric acid and thenwas lyophilized to afford1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{1-[(trans-4-hydroxycyclohexyl)amino]ethyl}azetidin-3-olhydrochloride (36 mg, 0.058 mmol, 55% yield): ¹H NMR (400 MHz, d₆-DMSO):8.61 (br s, 0.51H), 8.55 (br s, 0.5H), 8.49-8.33 (m, 1H), 8.08-7.90 (m,1H), 7.59 (dd, 1H), 7.39 (br d, 1H), 7.37-7.30 (m, 1H), 7.21 (br q, 1H),6.81 (br d, 1H), 6.77-6.65 (m, 1H), 4.20 (br d, 1H), 4.09-4.02 (m, 1H),3.97 (br d, 1H), 3.93-3.80 (m, 1H), 3.62-3.47 (m, 1H), 3.03-2.90 (m,1H), 2.07-1.93 (m, 2H), 1.93-1.77 (m, 2H), 1.54-1.06 (m, 8H); MS (EI)for C₂₄H₂₇F₃IN₃O₃: 590 (MH⁺).

Example 21(a)

Using the same or analogous synthetic techniques and substituting, asnecessary, with alternative reagents, the following compound of theinvention was prepared:1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{1-[(1,1-dimethylethyl)amino]ethyl}azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.63 (br s, 0.4H), 8.53 (br s, 0.6H), 7.56(dt, 1H), 7.40-7.34 (m, 1H), 7.32-7.26 (m, 1H), 7.25-7.13 (m, 1H),6.72-6.62 (m, 1H), 5.43 (br s, 1H), 4.14-3.56 (m, 4H), 2.69-2.53 (m,1H), 1.00-0.85 (br, 12H); MS (EI) for C₂₂H₂₅F₃IN₃O₂: 548 (MH⁺).

Example 22(a) and 22(b)1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol

-   -   and

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol

To a solution of 1,1-dimethylethyl2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate(368 mg, 0.94 mmol), prepared using procedures similar to thosedescribed in Reference 5, in dichloromethane (5 mL) was added DMAP (115mg, 0.94 mmol) and the resulting solution was cooled to 0° C.(R)-(−)-α-Methoxy-α-trifluoromethylphenylacetyl chloride (105 μL, 0.56mmol) was added to the solution by syringe and the mixture was allowedto warm to room temperature then stirred an additional 12 hours. Thesolution was then partitioned with saturated aqueous sodium bicarbonateand the organic phase dried over anhydrous magnesium sulfate thenfiltered and concentrated to an oily residue. Silica gel flashchromatography using hexanes:ethyl acetate 3:1 as eluent afforded theless polar 1,1-dimethylethyl(2R)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate(27.5 mg, 5% yield), the more polar 1,1-dimethylethyl(2S)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate(105 mg, 19% yield) and starting material (253 mg, 69% recovery).

The starting material thus recovered was taken into dichloromethane (3mL) followed by addition of DMAP (115 mg, 0.94 mmol) and(R)-(−)-α-methoxy-α-trifluoromethylphenylacetyl chloride (105 μL, 0.56mmol) and the mixture was allowed to stir at room temperature over 12hours. Proceeding as before afforded combined 1,1-dimethylethyl(2R)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate(46.6 mg, 8% yield), the more polar 1,1-dimethylethyl(2S)-2-(1-{[(phenylmethyl)oxy]carbonyl})-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate(228 mg, 41% yield) and starting material (100.8 mg, 27% recovery).

The starting material thus recovered was taken intotetrahydrofuran:dichloromethane (1:1, 2 mL) followed by addition of DMAP(47 mg, 0.39 mmol) and (R)-(−)-α-methoxy-α-trifluoromethylphenylacetylchloride (80 μL, 0.43 mmol) and the mixture was heated to 60° C. over 12hours. Proceeding as before afforded combined less polar1,1-dimethylethyl(2R)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate(144 mg, 26% yield). The chiral ester derivatives thus obtained wereagain subject to silica gel flash chromatography using hexanes:ethylacetate 3:1 as eluent to give the pure less polar 1,1-dimethylethyl(2R)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate(122.8 mg, 22% yield) and the more polar 1,1-dimethylethyl(2S)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate(177.6 mg, 32% yield) both as colorless amorphous residues.

1,1-Dimethylethyl(2R)-2-(1-{[(phenylmethyl)oxy]carbonyl}-3-{[(2R)-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanoyl]oxy}azetidin-3-yl)piperidine-1-carboxylate(122.8 mg, 0.21 mmol) was taken into methanol (4 mL) followed byaddition of IM aqueous sodium hydroxide (1 mL) and the resultingsolution was stirred for one hour at room temperature. The solution wasthen partitioned with ethyl acetate and IN aqueous hydrochloric acid.The organic layer was washed with brine, dried over anhydrous magnesiumsulfate then filtered and concentrated. The residue was purified bysilica gel flash chromatography using hexanes:ethyl acetate 2:1 to give1,1-dimethylethyl(2R)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate(60.8 mg, 81% yield) a colorless amorphous solid. 1,1-dimethylethyl(2S)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate(87.4 mg, 75% yield) was prepared analogously.

1,1-Dimethylethyl(2R)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate(60.8 mg, 0.16 mmol) and 10% Pd/C (30 mg) were taken into methanol (2mL) and the mixture hydrogenated at ambient pressure for one hour. Thesuspension was then filtered through a celite pad and concentrated thendried in vacuo to a colorless solid. The solid amine was taken into THF(1 mL) followed by addition of DIPEA (42 μL, 0.24 mmol) and3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (63 mg,0.16 mmol), prepared using procedures similar to those described inReference 1, and the mixture stirred at room temperature for 30 minutes.The reaction mixture was partitioned with ethyl acetate and 1 N aqueoushydrochloric acid and the organic layer washed with brine, dried overanhydrous magnesium sulfate then filtered and concentrated. Purificationof the residue by silica gel flash chromatography using hexanes:ethylacetate 3:2 as eluent afforded 1,1-dimethylethyl(2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate(74.9 mg, 74% yield) as an amorphous solid. 1,1-Dimethylethyl(2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate¹H NMR (400 MHz, CDCl₃): 8.53 (br s, 0.5H), 8.40 (br s, 0.5H), 7.41-7.38(dd, 1H), 7.34-7.31 (dt, 1H), 7.17-7.14 (m, 1H), 6.86-6.79 (m, 1H),6.63-6.587 (m, 1H), 4.24-3.90 (m, 4H), 3.37-3.23 (m, 1H), 2.90-2.80 (m,1H), 1.85-1.54 (m, 7H), 1.43 (s, 9H); MS (EI) for C₂₆H₂₉F₃IN₃O₄: 576(M−C₄H₉ ⁺).

1,1-dimethylethyl(2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate(74.9 mg, 0.12 mmol) was taken into methanol (1 mL) followed by additionof 4 N HCl in dioxane (1 mL) and the solution was stirred at roomtemperature for one hour. The solution was then concentrated and theresidue partitioned with chloroform and saturated aqueous sodiumbicarbonate. The organic layer was washed with brine, dried overanhydrous sodium sulfate then filtered and concentrated. Purification ofthe residue by silica gel flash chromatography using ethyl acetate thenconcentrated aqueous ammonia in chloroform and methanol (0.1:10:1) aseluents afforded1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol(57.3 mg) as a colorless amorphous solid. The free base was taken intomethanol (1 mL) then brought to about pH 1 by addition of 4 N HCl indioxane and the solution concentrated. The residue was triturated withethyl ether to afford a suspension. The solid was collected byfiltration to afford1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-olhydrochloride salt (49 mg, 72% yield) as a colorless solid. ¹H NMR (400MHz, CDCl₃): 8.43-8.39 (d, 1H), 7.41-7.38 (dd, 1H), 7.33-7.31 (dt, 1H),7.14-7.10 (m, 1H), 6.84-6.80 (m, 1H), 6.63-6.57 (m, 1H), 4.12-3.99 (m,4H), 3.10-3.08 (d, 1H), 2.72-2.69 (d, 1H), 2.64-2.62 (m, 1H), 1.61-1.58(m, 2H), 1.36-1.16 (m, 4H); MS (EI) for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺).

Using the same or analogous synthetic techniques and substituting, asnecessary, with alternative reagents, the following compounds of theinvention were prepared:

Example 22(c)

1,1-dimethylethyl(2S)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate:¹H NMR (400 MHz, CDCl₃): 8.52 (br s, 0.5H), 8.39 (br s, 0.5H), 7.41-7.38(dd, 1H), 7.34-7.31 (dt, 1H), 7.17-7.12 (m, 1H), 6.85-6.79 (m, 1H),6.63-6.57 (m, 1H), 4.25-3.88 (m, 4H), 3.34-3.26 (m, 1H), 2.80-2.90 (m,1H), 1.85-1.54 (m, 7H), 1.43 (s, 9H); MS (EI) for C₂₆H₂₉F₃IN₃O₄: 576(M−C₄H₉ ⁺).

Example 22(d)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-olhydrochloride: ¹H NMR (400 MHz, d₄-Methanol): 7.49-7.46 (dd, 1H),7.37-7.35 (dt, 1H), 7.35-7.30 (m, 1H), 7.10-7.04 (m, 1H), 6.64-6.59 (m,1H), 4.39-4.32 (dd, 1H), 4.21-4.18 (dd, 1H), 4.13-4.07 (m, 1H),3.97-3.88 (dd, 1H), 3.57-3.32 (m, 1H), 3.02-2.96 (dd, 1H), 1.90-1.50 (m,7H); MS (EI) for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺).

Example 22(e)

1-({2-[(4-bromo-2-chlorophenyl)amino]-3,4-difluorophenyl}carbonyl)-3-piperidin-2-ylazetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.56 (d, 1H), 7.29-7.38 (m, 2H),7.08-7.16 (m, 1H), 6.64-6.70 (m, 1H), 4.30-4.40 (m, 1H), 4.18-4.26 (m,1H), 4.04-4.14 (m, 1H), 3.90-4.00 (m, 1H), 3.16-3.26 (m, 2H), 2.86-2.96(m, 1H), 1.91 (s, 3H), 1.76-1.88 (m, 3H), 1.44-1.64 (m, 3H). MS (EI) forC₂₁H₂₁BrClF₂N₃O₂: 500 (M-H).

Example 22(f)

1-({2-[(4-bromo-2-fluorophenyl)amino]-3,4-difluorophenyl}carbonyl)-3-piperidin-2-ylazetidin-3-olacetate salt: ¹H NMR (400 MHz, DMSO): 8.52 (br s, 1H), 7.50 (d, 1H),7.35-7.15 (m, 3H), 6.88-6.79 (m, 1H), 4.15-3.96 (m, 1H), 3.84-3.78 (m,1H), 3.68-3.63 (m, 1H), 2.95-2.88 (m, 1H), 2.48-2.40 (m, 2H), 1.71-1.42(m, 3H), 1.25-1.14 (m, 2H), 1.03-0.90 (m, 1H); MS (EI) forC₂₁H₂₁BrF₃N₃O₂: 485 (MH⁺).

Example 22(g)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-pyrrolidin-2-ylazetidin-3-ol:¹H NMR (400 MHz, CD₃OD): 7.45 (dd, 1H), 7.37-7.31 (m, 1H), 7.30-7.25 (m,1H), 7.13-6.99 (m, 1H), 6.67-6.54 (m, 1H), 4.20-4.09 (m, 1H), 4.08-3.91(m, 2H), 3.88-3.79 (m, 1H), 3.27 (t, 1H), 2.99-2.89 (m, 1H), 2.88-2.81(m, 1H), 1.93-1.67 (m, 3H), 1.55-1.42 (m, 1H). MS (EI) forC₂₀H₁₉F₃IN₃O₂: 518 (MH⁺).

Example 22(h)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-methylpyrrolidin-2-yl)azetidin-3-olacetate (salt): ¹H NMR (400 MHz, CD₃OD): 7.46 (dd, 1H), 7.38-7.26 (m,2H), 7.12-6.99 (m, 1H), 6.66-6.56 (m, 1H), 4.37-3.87 (m, 4H), 2.94-2.82(m, 1H), 2.75-2.63 (m, 3H), 2.20-2.06 (m, 1H), 2.00-1.67 (m, 8H). MS(EI) for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺).

Example 22(i)

1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-ethylpyrrolidin-2-yl)azetidin-3-olacetate (salt): ¹H NMR (400 MHz, CD₃OD): 7.46 (d, 1H), 7.38-7.33 (m,1H), 7.32-7.27 (m, 1H), 7.12-7.01 (m, 1H), 6.66-6.57 (m, 1H), 4.34-3.89(m, 4H), 3.57 (t, 1H), 3.51-3.40 (m, 1H), 3.28-2.81 (m, 3H), 2.25-1.72(m, 8H), 1.31-1.18 (m, 3H). MS (EI) for C₂₂H₂₃F₃IN₃O₂: 546 (MH⁺).

Example 22(j)

1-({4-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-1-methyl-1H-benzimidazol-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-olacetate salt: ¹H NMR (400 MHz, dc-MeOH): 8.30 (s, 1H), 7.56 (s, 1H),7.42 (d, 1H), 7.24 (d, 1H), 6.34 (m, 1H), 4.20 (d, 2H), 3.92 (s, 3H),3.38-3.24 (m, 3H), 3.08 (bs, 1H), 2.88 (bs (1H), 1.90-1.70 (m, 3H),1.66-1.32 (m, 3H); MS (EI) for C₂₃H₂₄F₂IN₅O₂: 568 (MH⁺).

Example 22(k)

1-({7-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-1-methyl-1H-benzimidazol-5-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-olacetate salt: ¹H NMR (400 MHz, d₄-MeOH): 8.22 (s, 1H), 7.60 (s, 1H),7.42 (d, 1H), 7.26 (d, 1H), 6.46 (m, 1H), 4.21 (d, 2H), 4.06 (s, 3H),3.88 (m, 1H), 3.38-3.24 (m, 3H), 3.10 (bs, 1H), 2.88 (bs (1H), 1.88-1.70(m, 3H), 1.64-1.28 (m, 3H); MS (EI) for C₂₃H₂₄F₂IN₅SO₂: 568 (MH⁺).

Example 22(m)

4-[(4-bromo-2-fluorophenyl)amino]-3-fluoro-5-({3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}carbonyl)-1-methylpyridin-2(1H)-one:MS (EI) for C₂₁H₂₃BrF₂N₄O₃: 498 (MH⁺).

Example 22(n)

1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol:¹H NMR (400 MHz, d₆-DMSO): 8.79 (s, 1H), 8.04 (d, 1H), 7.91 (d, 1H),7.64 (dd, 1H), 7.55 (d, 1H), 6.95-7.02 (m, 1H), 4.38 (d, 1H), 4.15 (dd,1H), 3.99 (dd, 1H), 3.72 (q, 1H), 3.32-3.39 (m, 1H), 3.00-3.12 (m, 1H),1.93 (t, 3H), 1.51-1.70 (m, 3H); MS (EI) for C₂₂H₂₂ClFIN₅O₂: 532 (MH⁺).

Example 22(o)

1-({7-[(4-bromo-2-chlorophenyl)amino]-8-chloroimidazo[1,2-a]pyridin-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol:¹H NMR (400 MHz, d₄-MeOH): 8.85 (s, 1H), 8.06 (d, 1H), 7.91 (d, 1H),7.71 (d, 1H), 7.45 (d, 1H), 7.01 (d, 1H), 4.48 (d, 1H), 4.10-4.27 (m,2H), 3.87 (q, 1H), 3.37 (d, 2H), 3.02 (s, 1H), 1.88-1.94 (m, 3H),1.58-1.69 (m, 3H); C₂₂H₂₂BrCl₂N₅O₂: 540 (MH⁺).

Example 22(p)

1-({6-[(4-bromo-2-chlorophenyl)amino]-7-fluoro-3-methyl-1,2-benzisoxazol-5-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 8.50 (m, 1H), 7.51 (d, 1H), 7.42 (s, 1H), 7.26(dd, 1H), 6.79 (dd, 1H), 4.20-3.98 (br m, 4H), 3.11 (d, 1H), 2.77-2.50(br m, 5H), 1.80-1.15 (br m, 6H); MS (EI) for C₂₃H₂₃BrClFN₄O₃: 537(MH⁺).

Example 22(q)

1-({3-fluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol:¹H NMR (400 MHz, d₄-MeOH): 7.53 (2d, 1H), 7.46 (m, 2H), 7.16 (t, 1H),6.86 (m, 1H), 6.63 (m, 1H), 4.36 (m, 1H), 4.22 (m, 1H), 4.02 (m, 1H),3.88 (m, 1H), 3.08 (d, 1H), 2.66 (dd, 1H), 2.56 (m, 1H), 1.82 (bs, 1H),1.66 (d, 1H), 1.58 (d, 1H), 1.38 (m, 2H), 1.22 (m, 1H); MS (EI) forC₂₁H₂₂F₂IN₃O₂: 514 (MH⁺).

Example 22(r)

1-({4-fluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol:¹H NMR (400 MHz, d₄-MeOH): 7.42 (2d, 1H), 7.34-7.18 (m, 4H), 6.46 (m,1H), 4.10 (m, 2H), 3.84 (m, 2H), 3.04 (d, 1H), 2.52 (dd, 2H), 1.76 (bs,0.5H), 1.58 (m, 2.5H), 1.32 (m, 2H), 1.18 (m, 0.5H), 1.04 (m, 0.5H); MS(EI) for C₂₁H₂₂F₂IN₃O₂: 514 (MH⁺).

Example 22(s)

5-[(2-fluoro-4-iodophenyl)amino]-6-({3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}carbonyl)-2-methylpyridazin-3(2H)-one:¹H NMR (400 MHz, d₆-DMSO): 10.19 (s, 1H), 7.78 (dd, 1H), 7.59 (d, 1H),7.32 (t, 1H), 5.95 (s, 1H), 4.59 (q, 1H), 4.13-4.27 (m, 2H), 3.77 (d,1H), 3.62 (s, 3H), 3.02 (d, 2H), 2.71 (d, 1H), 1.78 (s, 1H), 1.68 (d,1H), 1.53 (d, 1H), 1.32 (s, 2H), 1.17 (t, 1H); MS (EI) for C₂₀H₂₃FIN₅O₃:528 (MH+).

Example 231-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}-3-nitroguanidineHydrochloride

To a mixture of2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-(1-oxa-5-azaspiro[2,3]hex-5-ylcarbonyl)aniline(0.15 g, 0.33 mmol), prepared using procedures similar to thosedescribed in Example 21, and nitroguanidine (0.1 g, 1.00 mmol) intetrahydrofuran (3.00 mL) an aqueous solution of sodium hydroxide (1.0mL, 2.0 mmol) was added and the reaction mixture was stirred at 70° C.for 16 hours. The reaction mixture was concentrated in vacuo. The crudeproduct was purified by reverse phase preparative HPLC. The fractionswere collected, and the solvent was concentrated. The residue waspartitioned with ethyl acetate. The organic layer was washed withsaturated aqueous sodium bicarbonate, brine and dried over anhydroussodium sulfate. Filtration and concentration resulted in an amorphousresidue, which was dissolved in methanol, and 4 N HCl in dioxane (80 μL,0.33 mmol) was added to the solution. A white precipitate formed and wascollected by filtration. The solid was washed with hexane, and dried toafford 76 mg (38%)1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}-3-nitroguanidinehydrochloride. ¹H NMR (400 MHz, d₄-MeOH): 7.46 (2d, 1H), 7.36 (m, 1H),7.29 (m, 1H), 7.02 (m, 1H), 6.63 (m, 1H), 4.22 (m, 1H), 4.01 (m, 2H),3.86 (m, 1H), 3.51 (d, 2H); MS (EI) for C₁₈H₁₆F₃IN₆O₄: 565 (MH⁺).

Example 23(a)

Using the same or analogous synthetic techniques and substituting, asnecessary, with alternative reagents, the following compounds of theinvention were prepared:1-cyano-3-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}guanidinehydrochloride. ¹H NMR (400 MHz, d₄-MeOH): 7.47 (2d, 1H), 7.36 (m, 1H),7.27 (m, 1H), 7.03 (m, 1H), 6.63 (m, 1H), 4.18 (m, 1H), 3.98 (m, 2H),3.80 (m, 1H), 3.43 (s, 2H); MS (EI) for C₁₉H₁₆F₃IN₆O₂: 545 (MH⁺).

Example 246-({3-[(ethylamino)methyl]-3-fluoroazetidin-1-yl}carbonyl)-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline

To 1,1-dimethylethyl[{1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}ethylcarbamate(27 mg, 0.044 mmol), prepared using procedures similar to those inExample 3 and followed by Boc-protection, in chloroform (2.5 mL) addedDAST (11.8 μL, 0.089 mmol) and stirred for 3.5 hr at room temperature.Quenched with water (15 mL), partitioned phases and extracted aqueousphase with chloroform (2×15 mL). The combined chloroform extracts weredried over sodium sulfate, filtered and the filtrate concentrated invacuo. The residue was purified on a silica gel column to afford1,1-dimethylethyl[{1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-fluoroazetidin-3-yl]methyl}ethylcarbamate(19.0 mg, 70%).

To the 1,1-dimethylethyl[{1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-fluoroazetidin-3-yl]methyl}ethylcarbamate(19.0 mg, 0.031 mmol) in acetonitrile (1.0 mL) added a solution 4.0Nhydrogen chloride in dioxane (1.0 mL). After 1.5 hr the solution wasconcentrated in vacuo. The residue was purified by preparative reversephase HPLC to afford the title compound (4.30 mg, 27%). ¹H NMR (400 MHz,CDCl₃): 8.25 (s, 1H), 7.33 (dd, 1H), 7.33-7.25 (m, 1H), 7.18-7.14 (m,1H), 6.84-6.77 (m, 1H), 6.63-6.58 (m, 1H), 4.33-4.05 (br m, 4H),3.07-2.95 (br m, 2H), 2.65 (q, 2H), 1.08 (t, 3H); MS (EI) forC₁₉H₁₈F₄IN₃O: 508 (MH⁺).

Example 253-(2-aminocyclohexyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol

A solution of 1-(trimethylsiloxy)cyclohexene (200 mg, 1.17 mmol) andbenzyl 3-oxoazetidine-1-carboxylate (289 mg, 1.41 mmol), prepared usingprocedures similar to those described in Reference 3, in tetrahydrofuran(3.90 mL) was cooled to −78° C. for 10 minutes followed by the additionof titanium tetrachloride (0.13 mL, 1.17 mmol). The reaction mixturestirred for an additional 5 hours at −78° C. The mixture was quenchedwith aqueous sodium bicarbonate and the aqueous layer was extracted withether (2×). The organic layer was separated, dried over anhydrous sodiumsulfate, filtered and the filtrate was concentrated in vacuo. Theresidue was purified on silica gel chromatography column (3:2hexanes/ethyl acetate) to afford benzyl3-hydroxy-3-(2-oxocyclohexyl)azetidine-1-carboxylate (328 mg, 37%). ¹HNMR (CDCl₃): 7.28-7.34 (m, 5H), 5.08 (s, 2H), 4.02 (d, 1H), 3.89 (d,1H), 3.87 (s, 1H), 3.55 (s, 1H), 2.71 (q, 1H), 2.29-2.43 (m, 2H), 2.11(s, 2H), 1.95 (s, 1H), 1.66 (d, 3H); MS (EI) for C₁₇H₂₁NO₄: 303 (MH+).

A solution of benzyl3-hydroxy-3-(2-oxocyclohexyl)azetidine-1-carboxylate (100 mg, 330 mmol)in methanol (1.60 mL) in the presence of ammonium acetate (191 mg, 2.48mmol was cooled to 0° C. for 1 hour. Sodium cyanoborohydride (81.5 mg,1.30 mmol) was added and the mixture was stirred at room temperature for16 hours. To the reaction mixture was added 6 N hydrogen chloride (800μL) and extracted with ethyl acetate. The aqueous layer was basifiedwith aqueous sodium bicarbonate (pH 9) and extracted withdichloromethane. The combined organic portion was dried over anhydroussodium sulfate, filtered and concentrated in vacuo to affordbenzyl-3-(2-aminocyclohexyl)-3-hydroxyazetidine-1-carboxylate (73.7 mg,73%). MS (EI) for C₁₇H₂₄N₂O₃: 305 (MH+).

To a solution ofbenzyl-3-(2-aminocyclohexyl)-3-hydroxyazetidine-1-carboxylate (202 mg,0.663 mmol) in dioxane-water (1:1, 2.5 mL) was added di-tert-butyldicarbonate (138 mg, 0.630 mmol) and solid sodium bicarbonate (112 mg,1.33 mmol). The reaction mixture was stirred at room temperature for 2hours and evaporated. The residue was partitioned between ethyl acetateand water. The organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to afford benzyl3-(2-tert-butoxycarbonylamino)cyclohexyl)-3-hydroxyazetidine-1-carboxylate(237 mg, 100%). ¹H NMR (CH₃OH): 7.15-7.21 (m, 5H), 5.45 (s, 0.5H), 5.20(d, 0.5H), 4.95 (s, 2H), 4.81 (s, 1H), 3.81 (d, 2H), 1.43-1.74 (m, 5H),1.39 (s, 1H), 1.31 (s, 1H), 1.20 (s, 1H). MS (EI) for C₂₂H₃₂N₂O₅: 405(MH+).

A solution of benzyl3-(2-tert-butoxycarbonylamino)cyclohexyl)-3-hydroxyazetidine-1-carboxylate(237 mg, 0.586 mmol) in ethyl acetate (2 mL) was hydrogenated over 10%palladium-carbon (200 mg, 0.586 mmol) at 40 psi for 16 hours. Thereaction mixture was filtered and concentrated in vacuo to providetert-butyl 2-(3-hydroxyazetidin-3-yl)cyclohexylcarbamate (181 mg, 100%).¹H NMR (CDCl₃): 5.10 (s, 1H), 4.80 ((s, 1H), 3.78-3.86 (m, 1H), 3.61 (d,1H), 3.57 (s, 1H), 3.36 (d, 1H), 1.77 (s, 2H). 1.40-1.53 (m, 1H), 1.36(d, 9H), 1.25 (s, 2H). MS (EI) for C₁₄H₂₆N₂O₃: 271 (MH+).

To a solution of tert-butyl2-(3-hydroxyazetidin-3-yl)cyclohexylcarbamate (181 mg, 0.669 mmol) and3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl fluoride (265 mg,0.669 mmol), prepared using procedures similar to those described inReference 1, in tetrahydrofuran (2.2 mL) was addedN,N-diisopropylethylamine (110 μL) at room temperature. After an hour,the reaction mixture was heated to 50° C. and stirred for 45 minutes, atwhich time it was cooled to room temperature and evaporated. The residuewas partitioned between ethyl acetate and 10% citric acid. The organiclayer was washed with aqueous sodium chloride, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to affordtert-butyl-2-(1-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl)-3-hydroxyazetidin-3-yl)cyclohexylcarbamate.This crude material was taken into the next step without furtherpurification.

Tert-butyl-2-(1-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl)-3-hydroxyazetidin-3-yl)cyclohexylcarbamatewas dissolved in a mixture of methanol (4 mL) and hydrogen chloride (4 Min dioxane) (3 mL). The solution was heated to reflux then cooled toroom temperature and stirred for 16 hours. The reaction mixture wasconcentrated and purified by reverse phase HPLC. The purified fractionswere evaporated to dryness and partitioned between ethyl acetate andaqueous sodium bicarbonate. The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo to afford an oil. Theresidue was taken up in methanol (2 mL) and was added hydrogen chloride(4M in dioxane) (700 μL) and evaporated to dryness to afford the titlecompound3-(2-aminocyclohexyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olhydrochloride (44.7 mg, 12%).

¹H NMR (400 MHz, d₆-DMSO): 8.58 (d, 1H), 7.59 (dd, 1H), 7.54 (s, 2H),7.38 (d, 1H), 7.33 (t, 1H), 7.16-7.25 (m, 1H), 6.69 (dt, 1H), 6.41 (s,1H), 4.26 (d, 0.51-), 4.17 (d, 0.5H), 4.04 (t, 1H), 3.90 (t, 1H), 3.79(d, 0.5H), 3.65-3.73 (m, 0.5H), 3.45-3.51 (m, 1H), 1.88 (s, 1H),1.65-1.88 (m, 2H), 1.47 (s, 4H), 1.16-1.37 (m, 2H); MS (EI) forC₂₂H₂₃F₃IN₃O₂: 546 (MH⁺).

Using the same or analogous synthetic techniques and substituting, asnecessary, with alternative reagents, the following compounds of theinvention were prepared:

Example 25(c)

3-(2-aminocyclopentyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;¹H NMR (400 MHz, d₆-DMSO): 8.56 (d, 1H), 7.82 (d, 1H), 7.59 (td, 1H),7.45 (s, 1H), 7.38 (d, 1H), 7.30-7.35 (m, 1H), 7.18-7.24 (m, 1H),6.68-6.72 (m, 1H0, 6.41 (s, 0.5H), 6.17 (s, 0.5H), 3.91-4.27 (m, 2.5H),3.78-3.86 (m, 1H), 3.65-3.73 (m, 1H), 3.44-3.52 (m, 0.5H), 2.19-2.26 (m,1H), 1.54-1.94 (m, 5H), 1.30-1.39 (m, 1H); MS (EI) for C₂₁H₂₁F₃IN₃O₂:532 (MH⁺).

Example 25(a) and Example 25(b)(±)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(trans)-2-hydroxycyclohexyl]azetidin-3-oland(+)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(cis)-2-hydroxycyclohexyl]azetidin-3-ol

The compounds of examples 25a and 25b were synthesized starting frombenzyl 3-hydroxy-3-(2-oxycyclohenyl)azetidine-1-carboxylate preparedaccording to the procedure given in example 25. The ketone was reducedto give benzyl 3-hydroxy-3-(2-hydroxycyclohexyl)azetidine-1-carboxylateas a mixture of racemic diastereomers which were subjected tohydrogenation to afford 3-(2-hydroxycyclohexyl)azetidin-3-ol.3-(2-hydroxycyclohexyl)azetidin-3-ol was then carried forward in acoupling step with 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoylfluoride in the usual manner. The coupled material thus obtained waspurified by preparative reverse phase HPLC where fraction 1 wastentatively assigned as(:)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(trans)-2-hydroxycyclohexyl]azetidin-3-ol(Example 25a) and fraction 2 was tentatively assigned as(±)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(cis)-2-hydroxycyclohexyl]azetidin-3-ol.

Example 25(a) First Eluting Fraction

¹H NMR (400 MHz, d₄-MeOH): 7.44 (2d, 1H), 7.34 (t, 1H), 7.25 (m, 1H),7.03 (m, 1H), 6.60 (m, 1H), 4.46 (d, 0.5H), 4.28 (d, 0.5H), 4.22 (d,0.5H), 3.98 (dd, 1H), 3.89 (d, 0.5H), 3.85 (s, 0.5H), 3.77 (d, 0.5H),3.56 (m, 1H), 1.90 (m, 1H), 1.46-1.74 (m, 4H), 0.98-1.32 (m, 4H); MS(EI) for C₂₂H₂₂F₃IN₂O₃: 547 (MH⁺).

Example 25(b). Second Eluting Fraction

¹H NMR (400 MHz, d₄-MeOH): 7.44 (2d, 1H), 7.33 (d, 1H), 7.26 (m, 1H),7.04 (m, 1H), 6.59 (dd, 1H), 4.20 (m, 1.5H), 4.19 (s, 0.5H), 4.00 (m,1.5H), 3.86 (dd, 1H), 3.74 (d, 0.5H), 1.76 (m, 2H), 1.50-1.68 (m, 5H),1.18-1.46 (m, 4H); MS (EI) for C₂₂H₂₂F₃IN₂O₃: 547 (MH⁺).

Example 26

3-({[(E)-1-amino-2-nitroethenyl]amino}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol

A solution of3-(aminomethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol(0.24 g, 0.5 mmol), prepared using procedures similar to those describedin Example 3, and commercially available1,1-bis(methylthio)-2-nitroethylene (0.083 g, 0.5 mmol) in ethanol (5mL) was stirred at 70° C. for 16 hours. The reaction mixture wasconcentrated in vacuo. The residue was partitioned between ethyl acetateand water. The organic layer was washed with brine, dried over sodiumsulfate, filtered and concentrated to afford 0.10 g, (39%)1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(Z)-1-(methylthio)-2-nitroethenyl]amino}methyl)azetidin-3-ol.MS (EI) for C₂₀H₁₈F₃IN₄O₄S: 595 (MH⁺).

To a solution of (0.05 g 0.08 mmol)1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(Z)-1-(methylthio)-2-nitrothenyl]amino}methyl)azetidin-3-olin ethanol (2 mL) was added ammonium hydroxide (0.1 mL, 0.8 mmol) andthe reaction mixture was stirred at 70° C. for 16 hours. The reactionmixture was concentrated in vacuo. The crude product was purified byreverse phase preparative HPLC. The fractions were collected and thesolvent was concentrated. The residue was partitioned with ethylacetate. The organic layer was washed with saturated aqueous sodiumbicarbonate, brine and dried over anhydrous sodium sulfate. Filtrationand concentration resulted in an amorphous residue, which was dissolvedin methanol, and 4 N HCl in dioxane (40 μL, 0.16 mmol) was added to thesolution. A white precipitate formed and was collected by vacuumfiltration. The solid was washed with hexane, and dried to afford 42 mg(87%)3-({[(E)-1-amino-2-nitroethenyl]amino}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olhydrochloride. ¹H NMR (400 MHz, d₄-MeOH): 7.58 (t, 0.5H), 7.44 (t,0.5H), 7.36 (m, 1H), 7.31 (m, 1H), 7.04 (m, 1H), 6.63 (m, 1H), 3.90-4.30(m, 4H) 3.72 (s, 2H); MS (EI) for C₁₉H₁₇F₃IN₅O₄: 564 (MH⁺).

Example 271-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1H-imidazol-2-ylmethyl)azetidin-3-ol

A solution of2-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (0.5 g,2.3 mmol) (prepared using procedures similar to those described inClader et. al. J of Med Chem. 1995, 38(10), 1600-7) in tetrahydrofuran(5 mL) was cooled to −78° C., and n-butyllithium was added (2.5 M inhexanes, 0.990 mL, 2.5 mmol). After 2 hours, 1,1-dimethylethyl3-oxoazetidine-1-carboxylate (0.60 g, 3.5 mmol), prepared usingprocedures similar to those described in Example 3, in 2.0 mLtetrahydrofuran was added and the solution was allowed to warm to roomtemperature and stirred overnight. The reaction mixture was quenchedwith an excess of saturated aqueous ammonium chloride solution andpartitioned between water and ethyl acetate. The layers were separatedand the aqueous layer was extracted with ethyl acetate (2×10 mL). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuo. Column chromatography (silica gel, 3:1hexanes/ethyl acetate) gave 0.37 g (41%) of3-{[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazol-2-yl]methyl}azetidin-3-ol:¹H NMR (400 MHz, CDCl₃): 6.96-6.92 (m, 1H), 5.23 (s, 2H), 3.98 (d, 2H),3.79 (d, 2H), 3.52-3.47 (m, 2H), 3.13 (s, 2H), 1.43 (s, 9H), 0.94-0.88(m, 2H), 0.00 (s, 9H).

3-{[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazol-2-yl]methyl}azetidin-3-ol(0.19 g, 0.49 mmol) was dissolved in dichloromethane (1.5 mL) andtrifluroacetic acid (1.5 mL) was added. The reaction mixture was stirredat room temperature overnight and the solvent was removed under vacuumto give 0.16 g of 3-(1H-imidazol-2-ylmethyl)azetidin-3-oltrifluoroacetate salt (87%). The crude residue was used without furtherpurification for the next step.

To a solution of 3-(1H-imidazol-2-ylmethyl)azetidin-3-oltrifluoroacetate salt (0.16 g, 0.42 mmol) and N,N-diisopropylethylamine(0.370 mL, 2.13 mmol) in tetrahydrofuran (2.0 mL)3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (0.17 g,0.42 mmol), prepared using procedures similar to those described inReference 1, was added and the reaction mixture was stirred for 3 hoursat room temperature. The solution was partitioned between ethyl acetateand saturated aqueous sodium bicarbonate and the organic layer was driedover sodium sulfate and concentrated in vacuo. Purification byreverse-phase HPLC followed by lyophilization of the pure fractions gave0.032 g (13%) ofl-({(3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1H-imidazol-2-ylmethyl)azetidin-3-olacetate salt: ¹H NMR (400 MHz, CD₃OD): 7.45 (dd, 1H), 7.38-7.33 (m, 1H),7.25-7.18 (m, 1H), 7.08-6.96 (m, 1H), 6.89 (s, 2H), 6.65-6.56 (m, 1H),4.33-4.22 (m, 1H), 4.17-4.00 (m, 2H), 3.91-3.80 (m, 1H), 3.08 (s, 2H),1.96 (s, 3H). MS (EI) for C₂₀H₁₆F₃IN₄O₂: 529 (MH⁺).

Example 283-[(1R)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol

To a solution of diisopropylamine (6.5 mL, 46.3 mmol) in THF (200 mL) at−78° C. was added butyllithium (17 mL of a 2.5 M solution in hexanes,42.5 mmol) over 5 min. The solution of lithium diisopropylamide wasstirred for 15 min at −78° C. A solution of(S)-4-benzyl-3-propionyl-2-oxazolidinone (9.0 g, 38.6 mmol) in T-IF (100mL) was added to the lithium diisopropylamide by addition funnel over 26min. The reaction temperature was kept below −70° C. during the courseof the addition. After the addition, the mixture was stirred for afurther 30 min at −78 OC. Then phenylmethyl 3-oxoazetidine-1-carboxylate(9.5 g, 46.3 mmol) was added by addition funnel over 25 minutes as asolution in THF (100 mL). Again, the reaction mixture was kept below−70° C. during the reagent addition. After stirring for an additional 1hour at −78° C., the reaction mixture was quenched with saturatedammonium chloride solution and was then allowed to warm to rt. Water wasadded to dissolve any precipitated ammonium chloride, and ethyl acetatewas added. The layers were partitioned, and the aqueous phase wasextracted twice with ethyl acetate. The combined organic extracts werewashed with 5% aqueous sodium bicarbonate, dried over sodium sulfate,filtered, and concentrated. The residue was purified by columnchromatography (50% ethyl acetate:50% hexanes) to provide phenylmethyl3-hydroxy-3-{(1R)-1-methyl-2-oxo-2-[(4S)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]ethyl}azetidine-1-carboxylateas a white crystalline solid (6.03 g, 13.8 mmol, 36% yield). ¹H NMR,(400 MHz, CDCl₃) δ 7.37 (m, 8H), 7.20 (d, 2H), 5.12 (s, 2H), 4.66 (m,1H), 4.27-4.20 (m, 2H), 4.10 (q, 1H), 4.03-3.93 (m, 3H), 3.28 (dd, 1H),2.77 (dd, 1H), 1.29 (d, 3H).

A solution of lithium hydroxide monohydrate (1.16 g, 27.6 mmol) in 30%hydrogen peroxide (13.2 mL, 138 mmol) was prepared and was subsequentlyadded slowly to a solution of phenylmethyl3-hydroxy-3-{(1R)-1-methyl-2-oxo-2-[(4S)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]ethyl}azetidine-1-carboxylate(6.03 g, 13.8 mmol) in THF (80 mL) and water (20 mL) at 0° C. After themixture was stirred for 1 h at rt, the hydrogen peroxide was quenchedcarefully with 1 M sodium sulfite (150 mL, 150 mmol). The THF wasremoved in vacuo, and the mixture was then acidified to pH=2 withconcentrated hydrochloric acid. The aqueous mixture was extracted twicewith ethyl acetate. The combined organic extracts were dried overmagnesium sulfate, filtered, and concentrated in vacuo. The resultingresidue was purified by column chromatography (gradient, 5% methanol:95% dichloromethane to 10% methanol: 90% dichloromethane) to provide(2R)-2-(3-hydroxy-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)propanoicacid as a colorless oil (2.77 g, 9.9 mmol, 72% yield). ¹H NMR (400 MHz,CDCl₃) δ 7.37-7.31 (m, 5H), 5.10 (s, 2H), 3.99 (s, 2H), 3.93 (s, 2H),2.88 (q, 1H), 1.28 (d, 3H); MS (1H) for C₁₄H₁₇NO₅: 280 (MH⁺).

To a solution of(2R)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)propanoicacid (2.77 g, 9.9 mmol) in toluene (100 mL) was added triethylamine(1.52 mL, 10.9 mmol) followed by diphenyl phosphoryl azide (2.24 mL,10.4 mmol). The mixture was heated to 80° C. for 2 h and was then cooledto rt. The volatile materials were removed in vacuo, and the residue waspurified by column chromatography (gradient: 50% hexanes: 50% ethylacetate up to 100% ethyl acetate). The desired product,(8R)-8-methyl-6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylic acidphenylmethyl ester, was isolated as a viscous, colorless syrup (1.84 g,6.6 mmol, 67% yield). ¹H NMR, (400 MHz, CDCl₃) δ 7.39-7.32 (m, 5H), 5.66(br s, 1H), 5.12 (s, 2H), 4.34 (dd, 1H), 4.30 (dd, 1H), 4.17 (dd, 1H),4.05 (dd, 1H), 3.98 (q, 1H), 1.34 (d, 3H).

To a solution of(8R)-8-methyl-6-oxo-5-oxa-2,7-diazaspiro[3.4]octane-2-carboxylic acidphenylmethyl ester (1.84 g, 6.6 mmol) in methanol (66 mL) was added wet10% palladium on carbon (50% by mass, 500 mg). The resulting suspensionwas stirred under 1 atm of hydrogen for 1 h. The catalyst was thenremoved by filtration through celite. The filtrate was concentrated invacuo to provide (8R)-8-methyl-5-oxa-2,7-diazaspiro[3.4]octan-6-one as awhite solid (0.99 g, quantitative yield). ¹H NMR (400 MHz, CDCl₃) δ 5.23(br s, 1H), 4.07 (d, 1H), 4.02 (d, 1H), 3.92 (d, 1H), 3.79 (d, 1H), 3.58(d, 1H), 1.38 (d, 3H); MS (EI) for C₆H₁₀N₂O₂: 143 (MH⁺).

A solution of (8R)-8-methyl-5-oxa-2,7-diazaspiro[3.4]octan-6-one (937mg, 6.6 mmol), acetic acid (0.756 mL, 13.2 mmol), and benzaldehyde (1.0mL, 9.9 mmol) in methanol (65 mL) was treated with sodiumcyanoborohydride (829 mg, 13.2 mmol) at rt for 30 min. The mixture wasthen cooled to 0° C., and 3 N hydrochloric acid (100 mL) was added. Themethanol was then removed in vacuo. The resulting aqueous solution waswashed with ethyl acetate. The ethyl acetate wash was back extractedwith 1 N hydrochloric acid, and the aqueous acidic phases were combinedand basified with potassium carbonate. The organic phase was discarded.The aqueous mixture was then extracted three times with ethyl acetate.The combined organic extracts were dried over magnesium sulfate,filtered, and concentrated in vacuo. The desired(8R)-8-methyl-2-(phenylmethyl)-5-oxa-2,7-diazaspiro[3.4]octan-6-one wasobtained in 93% purity as a milky colorless liquid (1.33 g, 5.73 mmol,87% yield). MS (EI) for C₁₃H₁₆N₂O₂: 233 (MH⁺).

To a solution of(8R)-8-methyl-2-(phenylmethyl)-5-oxa-2,7-diazaspiro[3.4]octan-6-one(1.33 g, 5.7 mmol) in dioxane (40 mL) and water (20 mL) was added bariumhydroxide octahydrate (9.0 g, 28.5 mmol), and the mixture was heated toreflux for 2 h. After cooling to rt, the mixture was acidified with 3 Nhydrochloric acid (10 mL) and dichloromethane (50 mL) was added. Thebiphasic mixture was treated with potassium carbonate (1.6 g, 11.4 mmol)and di-tert-butyl dicarbonate (2.11 g, 9.7 mmol). After stirringvigorously at rt for 17 h, solids were removed by filtration, and thelayers were partitioned. The aqueous phase was extracted withdichloromethane, and the organic extracts were combined and dried overmagnesium sulfate, filtered, and concentrated. The residue was taken upin methanol (60 mL) and was treated with potassium carbonate (3.0 g, 22mmol) added in two portions over 4 h at reflux. After cooling, themethanol was removed in vacuo, and the residual solids were loadeddirectly on to a silica column. After purification (5% methanol: 95%dichloromethane), 1,1-dimethylethyl{(1R)-1-[3-hydroxy-1-(phenylmethyl)azetidin-3-yl]ethyl}carbamate wasobtained as a colorless syrup (1.07 g, 3.5 mmol, 62% yield). MS (EI) forC₁₇H₂₆N₂O₃: 307 (MH⁺).

To a solution of 1,1-dimethylethyl{(1R)-1-[3-hydroxy-1-(phenylmethyl)azetidin-3-yl]ethyl}carbamate (1.07g, 3.5 mmol) in methanol was added wet 10% palladium on carbon (50% bymass, 250 mg). The resulting suspension was subjected to 1 atmosphere ofhydrogen for 7 h, and an additional 250 mg of catalyst was added overthe course of the reaction. The catalyst was then removed by filtrationthrough celite. The filtrate was then concentrated in vacuo to provide1,1-dimethylethyl [(1R)-1-(3-hydroxyazetidin-3-yl)ethyl]carbamate as acolorless syrup (800 mg, quantitative yield). MS (EI) for C₁₀H₂₀N₂O₃:161 (M−tert-butyl+H).

To a solution of 1,1-dimethylethyl[(1R)-1-(3-hydroxyazetidin-3-yl)ethyl]carbamate (200 mg, 0.92 mmol) indichloromethane (5 mL) was added diisopropylethylamine (228 μL, 1.38mmol) and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride(prepared according to the procedures described in Reference 1) (363 mg,0.92 mmol). The mixture was stirred at it for 16 h, after which thevolatile materials were removed in vacuo. The residue was purified bycolumn chromatography (50% hexanes:50% ethyl acetate) to provide1,1-dimethylethyl{(1R)-1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamateas a colorless film (333 mg, 0.56 mmol, 61% yield). ¹H NMR (400 MHz,CDCl₃) δ 8.47 (br s, 1H), 7.40 (dd, 1H), 7.32 (d, 1H), 7.12 (m, 1H),6.81 (m, 1H), 6.61 (m, 1H), 4.74 (br d, 1H), 4.22 (d, 1H), 4.15-4.07 (m,2H), 3.96 (br s, 1H), 3.77 (m, 1H), 1.43 (s, 9H), 1.18 (d, 3H); MS (EI)for C₂₃H₂₅F₃IN₃O₄: 536 (M−tert-butyl+H).

A solution of 1,1-dimethylethyl{(IR)-1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate(333 mg, 0.56 mmol) in methanol (10 mL) was treated with hydrochloricacid (4 N in dioxane, 1.4 mL, 5.6 mmol) at 60° C. for 30 min. Aftercooling, the volatile materials were removed in vacuo to provide3-[(1R)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olhydrochloride as a white solid (285 mg, 0.54 mmol, 97% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 8.56 (s, 1H), 7.83 (br s, 3H), 7.59 (dd, 1H), 7.39(d, 1H), 7.34 (m, 1H), 7.21 (q, 1H), 6.69 (m, 1H), 6.65 (s, 1H), 4.25(dd, 1H), 4.10 (dd, 1H), 3.98 (dd, 1H), 3.80 (m, 1H), 3.48 (m, 1H), 1.11(dd, 3H); MS (EI) for C₁₈H₁₇F₃IN₃O₂: 492 (MH⁺).

To establish the enantiomeric excess (ee) of this material,3-[(1R)-1-aminoethyl]-1-({^(3,4)-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olhydrochloride (21 mg, 0.040 mmol) was dissolved in dichloromethane (400μL) and was treated with diisopropylethylamine (20 μL, 0.12 mmol) and(R)-(−)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride at rt for 15min. An aliquot was removed and was analyzed by chiral HPLC. Thediastereomeric excessof(2S)-N-{(1R)-1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanamidewas found to be 91%, and by extrapolation the ee of3-[(1R)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olwas also assigned to be 91%.

Example 28a

Using the sequence described above, beginning with(R)-4-benzyl-3-propionyl-2-oxazolidinone,3-[(1S)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olwas prepared using similar procedures except that the phenylmethyl3-hydroxy-3-{(1S)-1-methyl-2-oxo-2-[(4R)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]ethyl}azetidine-1-carboxylaterequired additional recrystallizations from isopropanol. Using the samemethod described above in Example 28,3-[(1S)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olwas determined to have 98.4% cc. ¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (s,1H), 7.84 (br s, 3H), 7.59 (dd, 1H), 7.39 (d, 1H), 7.34 (m, 1H), 7.21(q, 1H), 6.69 (m, 1H), 6.65 (s, 1H), 4.25 (dd, 1H), 4.10 (dd, 1H), 3.98(dd, 1H), 3.80 (m, 1H), 3.48 (m, 1H), 1.11 (dd, 3H); MS (EI) forC₁₈H₁₇F₃IN₃O₂: 492 (MH⁺).

Example 28b

To3-[(1S)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol(87.4 mg, 0.18 mmol), prepared using procedures similar to thosedescribed in Example 28, was added formaldehyde (37% aqueous, 14 mg,0.18 mmol) in methanol (2 mL) and sodium borohydride (7 mg, 0.18 mmol).The mixture was stirred for 3 h at rt, after which sodium borohydride(16 mg, 0.42 mmol) was added. Upon stirring an additional 1.25 h, moreformaldehyde (37% aqueous, 1 drop) was added, and the mixture wasstirred 3 days at rt. A further small spatula (˜50 mg) of sodiumborohydride was then added, and the mixture was stirred at rt for 30min. After quenching with 1 N HCl, the reaction mixture was purifieddirectly by preparative HPLC. The clean material was converted to itshydrochloride salt to provide1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1S)-1-(methylamino)ethyl]azetidin-3-olas a yellow solid (21.7 mg, 0.040 mmol, 22% yield). ¹H NMR (400 MHz,CD₃OD) δ 7.47 (dd, 1H), 7.36 (d, 1H), 7.31 (m, 1H), 7.06 (q, 1H), 6.62(dt, 1H), 4.36 (dd, 1H), 4.21-3.91 (m, 3H), 3.44 (q, 1H), 2.66 (s, 3H),1.29 (br m, 3H); MS (EI) for C₁₉H₁₉F₃IN₃O₂: 506 (MH⁺).

Example 29

3-{[(1,1-Dimethylethyl)amino]methyl}-1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-ol

To a mixture of methyl 4-oxotetrahydrothiophene-3-carboxylate (1.75 g,11 mmol) (commercially available or prepared using procedures similar tothose described in Rossy et. al. J. Org. Chem. 1980, 45(4), 617-2) in 15mL of ethanol was added 2-fluoro-4-iodoaniline (2.6 g, 11 mmol) followedby addition of several drops of acetic acid. The mixture was refluxedfor 3 hrs. The mixture was cooled to room temperature and the productprecipitated. This product was filtered off, washed with ethyl acetate,ether, dried in vacuo to afford the methyl4-[(2-fluoro-4-iodophenyl)amino]-2,5-dihydrothiophene-3-carboxylate (1.7g, 42%). ¹HNMR(d₆-DMSO):9.80 (s, 1H), 7.71 (d, 1H), 7.49 (dd, 1H), 7.24(t, 1H), 4.10 (t, 2H), 3.79 (t, 2H), 3.69 (s, 3H); MS(EI) forC₁₂H₁₁FINO₂S: 380 (MH⁺).

To a mixture of methyl4-[(2-fluoro-4-iodophenyl)amino]-2,5-dihydrothiophene-3-carboxylate (1.2g, 3.16 mmol) in 10 ml of anhydrous toluene was added2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione (0.78 g, 3.16 mmol).The mixture was refluxed for 2 h. The mixture was cooled to 50° C. andconcentrated in vacuo to dryness and cooled to room temperature. To theresidue was added ethanol and the mixture was refluxed for severalminutes, cooled to room temperature and light blue crystalline productwas filtered off and dried in vacuo to afford methyl4-[(2-fluoro-4-iodophenyl)amino]thiophene-3-carboxylate (0.74 g, 62%).¹HNMR(d₆-DMSO): 8.78 (s, 1H), 8.42 (d, 1H), 7.64 (d, 1H), 7.46 (d, 1H),7.37 (t, 1H), 7.14 (s, 1H), 3.85 (s, 3H); MS(EI) for C₁₂H₉FINO₂S: 378(MH⁺).

A mixture of methyl4-[(2-fluoro-4-iodophenyl)amino]thiophene-3-carboxylate (0.74 g, 1.96mmol) in the solution of potassium hydroxide (0.3 g) in ethanol/water (4ml/4 ml) was heated up to 60° C. and stirred at this temperature for 30min. The mixture was cooled to room temperature, diluted with 4 ml ofwater and extracted with ether. The water layer was acidified with 1 NHCl to pH 2, the product precipitated and was filtered off, washedseveral times with water and dried in vacuo to afford4-[(2-fluoro-4-iodophenyl)amino]thiophene-3-carboxylic acid (0.59 g,83%). ¹H NMR (d₆-DMSO): 13.20 (s, 1H), 9.13 (s, 1H), 8.35 (d, 1H), 7.62(dd, 1H), 7.48-7.38 (m, 2H), 7.11 (s, 1H); MS(EI) for C₁₁H₇FINO₂S: 362(MH⁺).

4-[(2-fluoro-4-iodophenyl)amino]thiophene-3-carboxylic acid (200 mg,0.551 mmol), 4-(dimethylamino)pyridine (202 mg, 1.65 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (127 mg,0.662 mmol) were dissolved in DMF (3 mL). The mixture was stirred atambient for 5 minutes and then 3-(hydroxymethyl)azetidin-3-olhydrochloride (72 mg, 0.516 mmol) was added and the mixture was stirredfor 15 h. The mixture was partitioned between ethyl acetate and 20%citric acid. The aqueous portion was extracted with ethyl acetate. Thecombined organic portion was washed with 5% lithium chloride, saturatedsodium bicarbonate and brine, then was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue wascrystallized from dichloromethane to afford1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)-3-(hydroxymethyl)azetidin-3-ol(247 mg, 0.551 mmol, quantitative yield) as off-white crystals: MS (EI)for C₁₅H₁₄FIN₂O₃S: 449 (MH⁺).

1-({4-[(2-Fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)-3-(hydroxymethyl)azetidin-3-ol(247 mg, 0.551 mmol), was suspended in dichloromethane (10 mL) andtreated with 4-(dimethylamino)pyridine (80 mg, 0.661 mmol), and2,4,6-triisopropylbenzenesulfonyl chloride (183 mg, 0.604 mmol) atambient for 15 h. The mixture was adsorbed on to silica and purified bycolumn chromatography (silica gel, 30% ethyl acetate in hexanes) to give[1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl2,4,6-tris(1-methylethyl)benzenesulfonate (101 mg, 0.141 mmol, 26%yield): MS (EI) for C₃₀H₃₆FIN₂O₅S₂: 715 (MH⁺).

[1-({4-[(2-Fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl2,4,6-tris(1-methylethyl)benzenesulfonate (101 mg, 0.141 mmol) wasdissolved in tetrahydrofuran (2 mL) and was treated with sodium hydride(60 wt % dispersion in oil; 17 mg, 0.425 mmol) at ambient for 20minutes. Tetrahydrofuran (2 mL) and tert-butylamine (0.1 mL) were addedand the mixture was stirred at ambient for 16 h. The mixture wasconcentrated in vacuo and partitioned between ethyl acetate and water.The organic portion was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byreverse phase HPLC and the clean fractions were combined, neutralizedwith saturated sodium bicarbonate solution and the organic solvent wasremoved in vacuo. The remaining aqueous residue was extracted twice withethyl acetate. The combined organic portion was washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated in vacuo toafford3-{[(1,1-dimethylethyl)amino]methyl}-1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-ol(8 mg, 0.016 mmol, 11% yield): ¹H NMR (400 MHz, d₆-DMSO): 9.64 (br, 1H),8.08 (d, 1H), 7.59 (dd, 1H), 7.44 (dd, 1H), 7.36 (t, 1H), 7.12 (d, 1H),4.39 (d, 1H), 4.22 (d, 1H), 4.03 (d, 1H), 3.80 (d, 1H), 2.68 (br, 2H)1.04 (s, 9H); MS (EI) for C₁₉H₂₃FIN₃O₂S: 504 (MH⁺).

Using the same or analogous synthetic techniques and substituting, asnecessary, with alternative reagents, the following compounds of theinvention were prepared:

Example 29(a)

3-[(dimethylamino)methyl]-1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-ol:¹H NMR (400 MHz, CD₃OD): 7.91 (d, 1H), 7.46-7.41 (m, 2H), 7.33 (t, 1H),7.00 (d, 1H), 4.66 (s, 1H), 4.49 (s, 1H), 4.30 (s, 1H), 4.15 (s, 1H),3.54 (s, 1H), 3.17-3.13 (m, 3H), 2.90 (s, 2H), 1.87-1.83 (m, 3H); MS(EI)for C₁₇H₁₉FIN₃O₂S: 476 (MH⁺).

Example 29(b)

1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-amine:¹H NMR (400 MHz, CD₃OD): 7.90 (d, 1H), 7.46-7.41 (m, 2H), 7.31 (t, 1H),6.99 (d, 1H), 4.47 (br.s, 2H), 4.22-4.16 (m, 2H); MS(EI) forC₁₄H₁₃FIN₃OS: 418 (MH⁺).

Example 303-(1-aminoethyl)-1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)azetidin-3-ol

To a suspension of sodium hydride (72 mg, 1.75 mmol, 60% wt) intetrahydrofuran (1 mL) cooled to 0° C. was added nitroethane (125 μL,1.75 mmol). The suspension was allowed to warm to room temperature andwas stirred for 15 minutes, then cooled back to 0° C. To the suspensionwas added dropwise a solution of 1,1-dimethylethyl3-oxoazetidine-1-carboxylate (300 mg, 1.75 mmol, in 2 mL oftetrahydrofuran), prepared using procedures similar to those describedin Reference 3. The suspension was stirred at room temperature for 1hour. The reaction mixture was quenched by adding 20% aqueous citricacid, and then was partitioned with ethyl acetate. The aqueous portionwas extracted twice using ethyl acetate and the combined organic portionwas washed with saturated sodium bicarbonate, brine, dried over sodiumsulfate, filtered and concentrated in vacuo to afford a colorless oilthat was purified by column chromatography. Eluting with 30% ethylacetate in hexanes, the isolated product was concentrated in vacuo toafford 250 mg, 1.02 mmol (58%) of 1,1-dimethylethyl3-hydroxy-3-(1-nitroethyl)azetidine-1-carboxylate as a colorless oil ¹HNMR (400 MHz, DMSO): 6.46 (s, 1H), 5.01 (q, 1H), 4.24-3.97 (m, 2H),3.77-3.60 (m, 2H), 1.41 (d, 3H), 1.39 (s, 9H).

1,1-Dimethylethyl 3-hydroxy-3-(1-nitroethyl)azetidine-1-carboxylate wasdissolved in methanol (5 mL) and treated with 4 N HCl in dioxane. Thesolution was briefly heated to reflux and then was concentrated in vacuoto afford 178 mg, 0.98 mmol (96%) of 3-(1-nitroethyl)azetidin-3-olhydrochloride as a white solid. ¹H NMR (400 MHz, DMSO): 9.30 (br s, 1H),8.96 (br s, 1H), 5.12 (q, 1H), 4.44-4.38 (m, 1H), 4.22-4.17 (m, 1H),3.94-3.87 (m, 1H), 3.85-3.77 (m, 1H), 1.44 (d, 3H).

A solution of8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridine-6-carboxylicacid (150 mg, 0.35 mmol) (prepared using procedures similar to thosedescribed in US 2006030610 and US 2005054701), N,N-diisopropylethylamine(300 μL, 1.74 mmol), PyBOP (180 mg, 0.35 mmol) and3-(1-nitroethyl)azetidin-3-ol hydrochloride (76 mg, 0.42 mmol) indimethylformamide (3 mL) was stirred at room temperature for 15 hours.The reaction mixture was then partitioned between 5% aqueous lithiumchloride, and ethyl acetate. The aqueous portion was extracted twiceusing ethyl acetate. The combined organic portion was washed with 20%aqueous citric acid, brine, dried over sodium sulfate, filtered andconcentrated in vacuo to afford a brown residue which was purified bycolumn chromatography. Eluting with 5% methanol in dichloromethane, theisolated product was concentrated in vacuo to afford 195 mg, 0.35 mmol(100%) of1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-(1-nitroethyl)azetidin-3-olas a yellow foam. ¹H NMR (400 MHz, CDCl₃): 8.28 (s, 1H), 7.68 (s, 1H),7.59 (s, 1H), 7.43 (d, 1H), 7.31 (d, 1H), 7.23 (br s, 1H), 6.55-6.51 (m,1H), 6.02 (br s, 1H), 4.79 (q, 1H), 4.45-3.96 (4H), 1.56 (d, 3H). MS(EI) for C₂₀H₁₉ClFIN₆O₄: 560 (MH⁺).

To a solution of1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-(1-nitroethyl)azetidin-3-ol(195 mg 0.35 mmol) in tetrahydrofuran/water (5 mL, 4:1) was added ironpowder (193 mg, 3.5 mmol) and ammonium formate (438 mg, 7.0 mmol). Themixture was stirred at 80° C. for 1 hour, then cooled to roomtemperature and filtered through a pad of celite. The celite was washedthree times with boiling ethanol (20 mL). The filtrate was concentratedin vacuo and the residue was diluted with ethyl acetate. The precipitatewhich formed was filtered through a pad a celite and the filtrate waspartitioned with water. The aqueous portion was extracted twice withethyl acetate. The combined organic portion was washed with brine, driedover sodium sulfate, filtered and concentrated in vacuo to afford ayellow residue which was purified by preparative reverse phase HPLC. Theisolated product was concentrated in vacuo to afford mg, 0.05 mmol (15%)of3-(1-aminoethyl)-1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)azetidin-3-olacetate salt as a white solid. ¹H NMR (400 MHz, DMSO): 8.79 (s, 1H),8.00 (s, 1H), 7.61 (s, 1H), 7.54 (d, 1H), 7.32 (d, 1H), 6.54-6.48 (m,1H), 4.24-4.13 (m, 1H), 3.98-3.84 (m, 2H), 3.61-3.56 (m, 1H), 2.83 (q,1H), 0.92-0.88 (m, 3H); MS (EI) for C₁₉H₁₈ClFIN₅O₂: 530 (MH⁺).

Example 31 1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino] imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-piperidin-2-ylazetidin-3-ol

To a solution of 1,1-dimethylethyl2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate(595 mg, 1.52 mmol), prepared using procedures similar to thosedescribed in Reference 5, in methanol (5 mL) was added catalyticpalladium on carbon (5% wt). The heterogeneous mixture was stirred undera hydrogen gas atmosphere for 15 hours at ambient pressure and then wasfiltered. The filtrate was concentrated in vacuo to afford 385 mg, 1.50mmol (98%) of 1,1-dimethylethyl2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate as a colorless filmwithout further purification.

A solution of8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridine-6-carboxylicacid (78 mg, 0.18 mmol) (prepared using procedures similar to thosedescribed in US 2006030610 and US 2005054701), 1,1-dimethylethyl2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate (46.7 mg, 0.18 mmol),4-(dimethylamino)pyridine (66 mg, 0.55 mmol), and finally1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42 mg, 0.21mmol) in dimethylformamide (2 mL) was stirred at room temperature for 15hours. The reaction mixture was partition between 5% aqueous lithiumchloride and ethyl acetate and the aqueous portion was extracted twiceusing ethyl acetate. The combined organic portion was washed with 1 NHCl, brine, dried over sodium sulfate, filtered and concentrated invacuo to afford a brown residue which was purified by columnchromatography. Eluting with ethyl acetate, the isolated product wasconcentrated in vacuo to afford 101 mg, 0.15 mmol (83%) of1,1-dimethylethyl2-[1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylateas a white solid. The solid was immediately dissolved in methanol (5 mL)and 4 N HCl in dioxane was added. The solution was briefly heated toreflux and then was concentrated in vacuo. The resultant residue waspurified by preparative reverse phase HPLC. Isolated product wasconcentrated in vacuo to afford 36 mg, 0.06 mmol (40%) of1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-piperidin-2-ylazetidin-3-olacetate as a white solid. ¹H NMR (400 MHz, DMSO): 8.78 (s, 1H), 8.19 (s,0.5H), 8.15 (s, 0.5H), 8.00 (s, 1H), 7.62 (s, 1H), 7.55 (d, 1H), 7.31(d, 1H), 6.54-6.49 (m, 1H), 4.24-4.12 (m, 1H), 3.97-3.86 (m, 2H),3.63-3.56 (m, 1H), 2.98-2.90 (m, 1H), 2.50-2.40 (m, 1H), 1.72-1.61 (m,1H), 1.56-1.43 (m, 2H), 1.32-1.14 (m, 2H), 1.07-0.94 (m, 1H); MS (EI)for C₂₂H₂₂ClFIN₅O₂: 570 (MH⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative reagents, the following compounds of the invention wereprepared:

Example 31(a)

1-({4-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-1-methyl-1H-benzimidazol-6-yl}carbonyl)-3-piperidin-2-ylazetidin-3-olacetate salt: ¹H NMR (400 MHz, DMSO): 8.35 (s, 1H), 7.84-7.77 (m, 1H),7.54-7.49 (m, 2H), 7.25 (d, 1H), 6.31-6.25 (m, 1H), 4.04-3.92 (m, 2H),3.90 (s, 3H), 3.86-3.78 (m, 1H), 3.70-3.62 (m, 1H), 2.94-2.85 (m, 1H),2.45-2.32 (m, 2H), 1.66-1.36 (m, 3H), 1.26-1.08 (m, 2H), 1.01-0.80 (m,1H); MS (EI) for C₂₃H₂₄F₂IN₅O₂: 568 (MH⁺).

Example 31(a)

1-({7-[(4-bromo-2-chlorophenyl)amino]-8-chloroimidazo[1,2-a]pyridin-6-yl}carbonyl)-3-piperidin-2-ylazetidin-3-ol acetatesalt: ¹H NMR (400 MHz, DMSO): 8.87 (s, 1H), 8.29 (s, 0.5H), 8.21 (s,0.5H), 8.04 (s, 1H), 7.67-7.63 (m, 2H), 7.32 (d, 1H), 6.59 (d, 1H),4.35-4.22 (m, 1H), 4.08-3.98 (m, 2H), 3.72-3.67 (m, 1H), 2.96-2.88 (m,1H), 2.50-2.44 (m, 2H), 1.66-1.42 (m, 3H), 1.26-1.17 (m, 2H), 1.04-0.94(m, 1H); MS (EI) for C₂₂H₂₂BrCl₂N₅O₂: 540 (MH⁺).

Example 323-(1-Amino-3-hydroxypropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-olTrifluoroacetate Salt

Potassium tert-butoxide (1.393 g, 12.4 mmol) and[2-(1,3-dioxolan-2-yl)ethyl]-triphenylphosphonium bromide (5.51 g, 12.4mmol) were stirred in ether (30 mL) at ambient for 1 h. Phenylmethyl3-oxoazetidine-1-carboxylate (1.025 g, 5.0 mmol), prepared usingprocedures similar to those described in Reference 3, was added and themixture was stirred at 35° C. for 6 h and then at ambient for 4 days.Mixture was filtered through celite and the solid was washed with ether.The filtrate was washed with water, brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. Column chromatography(silica gel, 20% ether in hexanes) gave phenylmethyl3-[2-(1,3-dioxolan-2-yl)ethylidene]azetidine-1-carboxylate (220 mg,0.761 mmol, 15% yield): ¹H NMR (400 MHz, CDCl₃): 7.39-7.28 (m, 5H),5.43-5.35 (m, 1H), 5.11 (s, 2H), 4.89 (t, 1H), 4.56 (br d, 4H),4.00-3.92 (m, 2H), 3.91-3.83 (m, 2H), 2.27 (br t, 2H).

Phenylmethyl 3-[2-(1,3-dioxolan-2-yl)ethylidene]azetidine-1-carboxylate(220 mg, 0.761 mmol), and 4-methylmorpholine N-oxide (287 mg, 2.45 mmol)were dissolved in acetone/water (4:1; 10 mL) and osmium tetroxide (4 wt.% in water; 0.05 mL) was added. The solution was stirred at ambient for20 h, then was quenched with saturated sodium bisulfite (2 mL) andconcentrated in vacuo. The residue was partitioned between ethyl acetateand brine. The aqueous portion was extracted with ethyl acetate. Thecombined organic portion was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. Columnchromatography (silica gel, ethyl acetate) gave phenylmethyl3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]-3-hydroxyazetidine-1-carboxylate(244 mg, 0.755 mmol, 99% yield): ¹H NMR (400 MHz, CDCl₃): 7.38-7.28 (m,5H), 5.11-5.07 (m, 3H), 4.14-4.01 (m, 4H), 3.96-3.86 (m, 5H), 3.47 (d,1H), 2.97-2.94 (m, 1H), 1.98-1.84 (m, 2H).

Phenylmethyl3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]-3-hydroxyazetidine-1-carboxylate(235 mg, 0.728 mmol) was dissolved in methanol (5 mL) and treated with 5wt % palladium on carbon (50 mg) under hydrogen at ambient for 1.5 h.The mixture was filtered and the filtrate was concentrated in vacuo toafford 3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (0.729mmol): MS (EI) for C₈H₁₅NO₄: 190 (MH⁺).

J 3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (287 mg,0.730 mmol), prepared using procedures similar to those described inU.S. Pat. No. 7,019,033, 4-(dimethylamino)pyridine (178 mg, 1.46 mmol)and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (168 mg,0.88 mmol) were dissolved in DMF (3 mL). The mixture was stirred atambient for 10 minutes and then3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (0.729 mmol) inDMF (2 mL) was added and the mixture was stirred for 15 h. The mixturewas partitioned between ethyl acetate and 5% lithium chloride. Theorganic portion was washed with 20% citric acid, saturated sodiumbicarbonate and brine, then was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. Column chromatography (silica gel,gradient 90% ethyl acetate in hexanes to 100% ethyl acetate) gave1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol(148 mg, 0.262 mmol, 36% yield): MS (EI) for C₂₁H₂₀F₃IN₂O₅: 565 (MH⁺).

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol(148 mg, 0.262 mmol), was dissolved in dichloromethane (10 mL) andtreated with 4-(dimethylamino)pyridine (38 mg, 0.31 mmol), triethylamine(0.036 mL, 0.262 mmol) and 2,4,6-triisopropylbenzenesulfonyl chloride(303 mg, 1.0 mmol) at 35° C. for 15 h. 2,4,6-Triisopropylbenzenesulfonylchloride (100 mg, 0.33 mmol) was added and the mixture was stirred at35° C. for 3.5 h. The mixture was adsorbed on to silica and purified bycolumn chromatography (silica gel, 40-50% ethyl acetate in hexanes andthen 100% ethyl acetate) to give1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-(1,3-dioxolan-2-yl)ethyl2,4,6-tris(l-methylethyl)benzenesulfonate (30 mg, 0.0361 mmol, 14%yield): MS (EI) for C₃₆H₄₂F₃IN₂O₇S: 831 (MH⁺).

1-[1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-(1,3-dioxolan-2-yl)ethyl2,4,6-tris(1-methylethyl)benzenesulfonate (50 mg, 0.060 mmol) wasdissolved in tetrahydrofuran (1 mL) and was cooled to 0° C. Sodiumhydride (60 wt % dispersion in oil; 7 mg, 0.18 mmol) was added and themixture was stirred at 0° C. for 45 minutes. The mixture was quenchedwith saturated sodium bicarbonate solution and partitioned with ethylacetate. The aqueous portion was extracted with ethyl acetate. Thecombined organic portion was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. Columnchromatography (silica gel, 50% ethyl acetate in hexanes) gave6-{[2-(1,3-dioxolan-2-ylmethyl)-1-oxa-5-azaspiro[2.3]hex-5-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline(31 mg, 0.057 mmol, 94% yield): MS (EI) for C₂₁H₁₈F₃N₂O₄: 547 (MH⁺).

6-{[2-(1,3-Dioxolan-2-ylmethyl)-1-oxa-5-azaspiro[2.3]hex-5-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline(31 mg, 0.057 mmol) was dissolved in dimethylformamide (0.5 mL) andsodium azide (20 mg, 0.308 mmol) was added. The mixture was stirred atambient for 22 h. The mixture was partitioned between ethyl acetate and5% lithium chloride. The aqueous portion was extracted with ethylacetate. The combined organic portion was washed with water, brine, thenwas dried over anhydrous sodium sulfate, filtered and concentrated invacuo. Column chromatography (silica gel, 50% ethyl acetate in hexanes)gave3-[1-azido-2-(1,3-dioxolan-2-yl)ethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol(25 mg, 0.042 mmol, 74% yield): MS (EI) for C₂₁H₁₉F₃IN₅O₄: 590 (MH⁺).

3-[1-Azido-2-(1,3-dioxolan-2-yl)ethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol(24 mg, 0.041 mmol) was dissolved in tetrahydrofuran (0.5 mL) andtreated with 5% aqueous hydrochloric acid (0.5 mL) at ambient for 15 h.The mixture was neutralised with saturated sodium bicarbonate solutionand was extracted twice with ethyl acetate. The combined organic portionwas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to afford3-azido-3-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]propanal(21 mg, 0.0385 mmol) which was suspended in ethanol (2 mL) and treatedwith sodium borohydride (5 mg, 0.132 mmol) at ambient for 2 h. Themixture was quenched with acetic acid (4 drops) and concentrated invacuo. The residue was partitioned between saturated sodium bicarbonatesolution and ethyl acetate. The aqueous portion was extracted with ethylacetate. The combined organic portion was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Columnchromatography (silica gel, 70-80% ethyl acetate in hexanes) gave3-(1-azido-3-hydroxypropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol(14 mg, 0.0255 mmol, 62% yield from3-[1-azido-2-(1,3-dioxolan-2-yl)ethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol):¹H NMR (400 MHz, CDCl₃): 8.33 (br s, 1H), 7.40 (dd, 1H), 7.32 (br d,1H), 7.13 (br t, 1H), 6.83 (br q, 1H), 6.61 (ddd, 1H), 4.32-3.94 (m,4H), 3.92-3.84 (m, 1H), 3.82-3.71 (m, 2H), 2.56 (br, 1H), 1.94 (br, 2H),1.26 (br, 1H); MS (EI) for C₁₉H₁₇F₃IN₅O₃: 548 (MH⁺).

3-(1-Azido-3-hydroxypropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol(14 mg, 0.0255 mmol) was dissolved in tetrahydrofuran and water (1:1,0.5 mL) and polymer supported triphenylphosphine (˜3 mmol/g; 20 mg, 0.06mmol) was added. The mixture was stirred at 55° C. for 1 h.Triphenylphosphine (10 mg, 0.038 mmol) was added and the mixture wasstirred at 55° C. for 1.5 h. The mixture was filtered and the filtratewas purified by reverse phase HPLC to afford3-(1-amino-3-hydroxypropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-oltrifluoroacetate salt (1.7 mg, 0.003 mmol, 10% yield): ¹H NMR (400 MHz,CD₃OD): 7.47 (dd, 1H), 7.36 (br d, 1H), 7.33-7.28 (m, 1H), 7.05 (br q,1H), 6.62 (ddd, 1H), 4.38-4.26 (m, 1H), 4.18-4.00 (m, 2H), 3.98-3.88 (m,1H), 3.78-3.67 (m, 2H), 3.61-3.56 (m, 1H), 1.87-1.70 (m, 2H); MS (EI)for C₁₉H₁₉F₃IN₃O₃: 522 (MH⁺).

Example 331-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(6-methylpiperidin-2-yl)azetidin-3-ol

To a solution of N,N-diisopropylamine (1.6 mL, 11.2 mmol) cooled to −78°C. in THF (15 mL) was added a 2.5 M solution of n-BuLi in hexane (4.5mL, 11.2 mmol) dropwise over 5 minutes and the mixture was stirred atthis temperature for an addition 15 minutes.6-methyl-1-(phenylmethyl)piperidine-2-carbonitrile (2.4 g, 11.2 mmol)(prepared using procedures similar to those in Bonin et. al. Tet. Lett.1982, 23(33), 3369-72) in THF (10 mL) was then added dropwise over 20minutes and the reaction mixture was stirred for a further 30 minutes.Next a solution of 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (1.3g, 7.5 mmoL), prepared using procedures similar to those in Example 3,in THF (10 mL) was added dropwise over 30 minutes. The reaction mixturewas gradually warmed to room temperature and allowed to stir overnight.The reaction mixture was quenched with 10% citric acid and extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith water, brine, dried over anhydrous sodium sulfate then filtered andconcentrated in vacuo to give crude product as yellow oil. Furtherpurification by flash chromatography (30% ethyl acetate in hexanes)afforded 1,1-dimethylethyl3-[2-cyano-6-methyl-1-(phenylmethyl)piperidin-2-yl]-3-hydroxyazetidine-1-carboxylateas a pale yellow oil (0.2 g, 7% yield). ¹H NMR (400 MHz, CDCl₃):7.17-7.40 (m, 5H), 4.42 (d, 1H), 4.04-4.18 (m, 1H), 3.83-4.00 (m, 1H),3.70-3.75 (m, 2H), 1.70-1.87 (m, 4H), 1.45 (s, 3H), 1.41 (s, 9H),1.22-1.26 (m, 1H), 1.13-1.18 (m, 2H); MS (EI) for C₂₂H₃₁N₃O₃: 386 (MH⁺).

To a stirred solution of 1,1-dimethylethyl3-[2-cyano-6-methyl-1-(phenylmethyl)piperidin-2-yl]-3-hydroxyazetidine-1-carboxylate(180 mg, 0.47 mmol) in ethanol (1 mL) was added acetic acid (53.5 μL,0.94 mmol) followed by sodium cyanoborohydride (58.7 mg, 0.94 mmol) andthe reaction mixture stirred at 70° C. overnight After cooling to roomtemperature the suspension was filtered through celite and the solidwashed with additional ethanol. The filtrate was concentrated in vacuoand taken up in ethyl acetate (30 mL). The organic layer was washed with2 M sodium hydroxide solution. The sodium hydroxide layer was separatedand washed with ethyl acetate (10 mL). The combined organic layers werewashed with brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo to give crude 1,1-dimethylethyl3-hydroxy-3-[6-methyl-1-(phenylmethyl)piperidin-2-yl]azetidine-1-carboxylateas yellow oil (60 mg, 36% yield). Crude product was used further withoutpurification. ¹H NMR (400 MHz, CDCl₃): 7.22-7.35 (m, 5H), 4.08 (d, 1H),3.85-3.96 (m, 3H), 3.57 (d, 1H), 3.33-3.36 (m, 1H), 2.91-3.06 (m, 2H),1.63-1.70 (m, 4H), 1.44 (s, 9H), 1.23 (d, 3H), 1.05 (d, 2H); MS (EI) forC₂₁H₃₂N₂O₃: 361 (MH⁺).

To a solution of 1,1-dimethylethyl3-hydroxy-3-[6-methyl-1-(phenylmethyl)piperidin-2-yl]azetidine-1-carboxylate(60 mg, 0.16 mmol) in methanol (0.5 mL) was added hydrogen chloride (4Nin dioxane, 0.5 mL) and the reaction mixture stirred at 60° C. for onehour. The reaction mixture was cooled to room temperature andconcentrated in vacuo and aezotroped 3 times from methanol and diethylether. On drying the hydrochloride salt of3-[6-methyl-1-(phenylmethyl)piperidin-2-yl]azetidin-3-ol was obtained asa dark brown residue (40 mg, 81% yield), which was used further withoutpurification. ¹H NMR (400 MHz, CD₃OD): 7.58-7.63 (m, 2H), 7.47-7.49 (m,3H), 4.78 (d, 1H), 4.44-4.62 (m, 2H), 4.29 (s, 2H), 4.22-4.26 (m, 1H),4.12-4.18 (m, 1H), 4.08 (s, 1H), 1.60-2.00 (m, 8H), 1.48 (d, 3H); MS(EI) for C₁₆H₂₅ClN₂O: 261 (MH⁺).

To a solution of3-[6-methyl-1-(phenylmethyl)piperidin-2-yl]azetidin-3-ol hydrochloride(40 mg, 0.13 mmol) in ethyl acetate (3 mL) was added acetic acid (0.5mL) and Pd/C (50 mg) and the mixture was hydrogenated at 35 psi for 3hours. The reaction mixture was filtered through celite. The filtratewas concentrated in vacuo. The obtained residue was dissolved in a smallamount of ethyl acetate and concentrated hydrochloric acid was added andthe mixture was concentrated in vacuo to give the crude dihydrochloridesalt of 3-[6-methylpiperidin-2-yl]azetidin-3-ol (20 mg, 54%). The crudeproduct was used further without purification. ¹H NMR (400 MHz, CD₃OD):4.20-4.40 (m, 1H), 4.00-4.10 (m, 1H), 3.60-3.90 (m, 2H), 1.50-2.00 (m,6H), 1.45 (d, 3H), 1.26-1.30 (m, 1H); MS (EI) for C₉H₂₀Cl₂N₂O: 171(MH⁺).

To a 0° C. solution of 3-[6-methylpiperidin-2-yl]azetidin-3-oldihydrochloride (20 mg, 0.08 mmol) in DMF (1 mi.) was addedN,N-diisopropylethylamine (42 μL, 0.26 mmol) followed by3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino] benzoyl fluoride (32 mg,0.08 mmol), prepared using procedures similar to those described inReference 1, and the reaction mixture stirred at 0° C. for 30 min. Themixture was diluted with acetonitrile and purified by preparativereverse phase HPLC (CH₃CN/H₂O with 0.1% TFA). Fractions were collectedand lyophilized to give1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(6-methylpiperidin-2-yl)azetidin-3-olacetate salt (7 mg, 16% yield) as a white solid. ¹H NMR (400 MHz,CD₃OD): 7.44-7.50 (m, 1H), 7.34-7.37 (m, 1H), 7.28-7.32 (m, 1H),7.02-7.12 (m, 1H), 6.60-6.63 (m, 1H), 4.10-4.30 (m, 2H), 3.95-4.09 (m,2H), 3.80-3.95 (m, 1H), 3.55-3.65 (m, 1H), 3.34-3.36 (m, 1H), 1.90 (s,3H), 1.62-1.84 (m, 6H), 1.40-1.52 (m, 1H), 1.33 (d, 3H); MS (EI) forC₂₂H₂₃F₃IN₃O₂: 546 (MH⁺).

Example 341-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-piperazin-2-ylazetidin-3-ol

To a solution of commercially available1,4-bis(phenylmethyl)piperazine-2,5-dione (2.0 g, 6.8 mmol) in dry THF(50 mL) at −78° C. was added lithium diisopropylamide (2.0 M solution inheptane/THF/ethylbenzene, 3.4 mL, 6.8 mmol). The resulting reddish brownsuspension was stirred for 23 min at −78° C., and then a solution of1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (770 mg, 4.5 mmol) in THF(10 mL) was added over 30 min by syringe pump. The mixture became abright yellow solution as it was allowed to warm to room temperatureover 3 hours. The mixture was quenched with saturated aqueous ammoniumchloride. Water was added to dissolve precipitated salts, and theresulting mixture was extracted twice with ethyl acetate. The combinedorganic extracts were dried over magnesium sulfate, filtered, andconcentrated. The residue was purified by column chromatography (60%ethyl acetate: 40% hexanes) to provide 1,1-dimethylethyl3-[3,6-dioxo-1,4-bis(phenylmethyl)piperazin-2-yl]-3-hydroxyazetidine-1-carboxylateas a colorless foam (1.04 g, 223 mmol, 50% yield). ¹H NMR (400 MHz,CDCl₃): 7.39-7.29 (m, 7H), 7.23-7.19 (m, 3H), 5.34 (d, 1H), 4.82 (d,1H), 4.58 (d, 1H), 4.37 (d, 1H), 4.37 (d, 1H), 4.22 (d, 1H), 4.15 (s,1H), 4.08 (d, 1H), 3.97 (d, 1H), 3.75 (d, 1H), 3.74 (d, 1H), 3.67 (d,1H), 3.64 (br s, 1H), 1.43 (s, 9H).

A solution of 1,1-dimethylethyl3-[3,6-dioxo-1,4-bis(phenylmethyl)piperazin-2-yl]-3-hydroxyazetidine-1-carboxylate(1.04 g, 2.2 mmol) in methanol (10 mL) was treated with hydrogenchloride in dioxane (4 N, 5.5 mL, 22 mmol) at 60° C. for 25 min. Aftercooling to room temperature the solution was concentrated. Ethyl acetateand 2 N hydrochloric acid were added to the residue and the phases wereseparated. The organic phase was discarded. The aqueous phase wasbasified with 5 M sodium hydroxide and the resulting solution wasextracted 4 times with ethyl acetate. The combined organic extracts weredried over magnesium sulfate, filtered, and concentrated. The residuewas purified by column chromatography (85% dichloromethane: 14%methanol: 1% aqueous ammonium hydroxide) to provide3-(3-hydroxyazetidin-3-yl)-1,4-bis(phenylmethyl)piperazine-2,5-dione asa colorless film (493 mg, 1.35 mmol, 61% yield). ¹H NMR (400 MHz,CDCl₃): 7.39-7.28 (m, 6H), 7.25-7.20 (m, 4H), 5.39 (d, 1H), 4.80 (d,1H), 4.44 (d, 1H), 4.36 (d, 1H), 4.26 (d, 1H), 4.11 (s, 1H), 3.97 (d,1H), 3.83 (d, 1H), 3.71 (d, 1H), 3.27 (m, 2H); MS (EI) for C₂₁H₂₃N₃O₃:366 (MH⁺).

A solution3-(3-hydroxyazetidin-3-yl)-1,4-bis(phenylmethyl)piperazine-2,5-dione(493 mg, 1.35 mmol) in ethyleneglycol dimethylether (12 mL) was treatedwith sodium borohydride (511 mg, 13.5 mmol) followed by slow addition ofboron trifluoride-diethyl etherate. The reaction mixture was then heatedto reflux for 3 hours. After cooling to 0° C., methanol (17 mL) wasadded followed by careful addition of concentrated hydrochloric acid (7mL). The resulting mixture was heated to reflux for 70 minutes. Aftercooling to room temperature, insoluble residue was removed byfiltration. The filtrate was concentrated to an aqueous mixture of about10 mL in volume. This mixture was cooled to 0° C. and was then basifiedto pH 10 with 5 M sodium hydroxide (approximately 17 mL).Dichloromethane (10 mL) was then added followed by di-tert-butyldicarbonate (442 mg, 2.03 mmol). The mixture was warmed to roomtemperature and stirred for 15 minutes. The layers were separated andthe aqueous phase was extracted twice with dichloromethane. The organicextracts were combined, dried over magnesium sulfate, filtered, andconcentrated. The residue was purified by column chromatography (70%hexanes: 30% ethyl acetate) to provide 1,1-dimethylethyl3-[1,4-bis(phenylmethyl)piperazin-2-yl]-3-hydroxyazetidine-1-carboxylateas a white foam (408 mg, 0.93 mmol, 69% yield). ¹H NMR (400 MHz, CDCl₃):7.35-7.24 (m, 10H), 4.12 (br s, 1H), 3.88 (d, 1H), 3.78-3.65 (m, 4H),3.53 (d, 1H), 3.43 (d, 1H), 3.21 (m, 1H), 2.80 (br s, 1H), 2.66 (m, 1H),2.57-2.37 (m, 4H), 1.41 (s, 9H); MS (EI) for C₂₆H₃₅N₃O₃: 438 (MH⁺).

To a solution of 1,1-dimethylethyl3-[1,4-bis(phenylmethyl)piperazin-2-yl]-3-hydroxyazetidine-1-carboxylate(408 mg, 0.93 mmol) in methanol (15 mL) was added 10% palladium oncarbon (wet), and the resulting suspension was subjected to anatmosphere of hydrogen for 21 hours. The catalyst was removed byfiltration through celite, and the filter cake was rinsed with methanol.The combined filtrate was concentrated to provide 1,1-dimethylethyl3-hydroxy-3-piperazin-2-ylazetidine-1-carboxylate as a brown syrup (227mg, 0.88 mmol, 95% yield). ¹H NMR (400 MHz, CDCl₃): 3.94-3.76 (m, 5H),3.12 (m, 1H), 3.01 (m, 1H), 2.94-2.81 (m, 3H), 2.78-2.70 (m, 2H); MS(EI) for C₁₂H₂₃N₃O₃: 258 (MH⁺).

To a solution of 1,1-dimethylethyl3-hydroxy-3-piperazin-2-ylazetidine-1-carboxylate (227 mg, 0.88 mmol)and N,N-diisopropylethylamine (436 μL, 2.64 mmol) in THF (5 mL) wasadded 2-nitrobenzenesulfonyl chloride (195 mg, 0.88 mmol). The mixturewas stirred at room temperature for 2 hours. The solution wasconcentrated and the residue was purified by column chromatography (95%dichloromethane: 5% methanol) to provide 1,1-dimethylethyl3-hydroxy-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidine-1-carboxylateas a white foam (308 mg, 0.70 mmol, 79% yield). ¹H NMR (400 MHz, CDCl₃):7.98 (m, 1H), 7.72 (m, 2H), 7.64 (m, 1H), 3.96 (d, 1H), 3.94 (d, 1H),3.85 (d, 1H), 3.79 (d, 1H), 3.79-3.73 (m, 2H), 3.11 (m, 1H), 3.05 (dd,1H), 3.00 (br s, 1H), 2.94 (dt, 1H), 2.78 (dt, 1H), 2.68 (dd, 1H), 1.45(s, 9H).

To a solution of 1,1-dimethylethyl3-hydroxy-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidine-1-carboxylate(308 mg, 0.70 mmol) in methanol (10 mL) was added HCl in dioxane (4 N,1.75 mL, 7.0 mmol), and the mixture was heated to 60° C. for 30 minutes.The solution was concentrated to provide3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidin-3-ol as a stickywhite solid. This material was dissolved in dichloromethane (7 mL). Tothe solution was added N,N-diisopropylethylamine (1.16 mL, 7.0 mmol)followed by 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoylfluoride (277 mg, 0.7 mmol), prepared using procedures similar to thosedescribed in Reference 1, and the resulting mixture was stirred at roomtemperature for 16 hours. The solution was concentrated and the residuewas purified by column chromatography (95% dichloromethane: 5% methanol)to provide1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidin-3-olas a pale yellow foam (453 mg, 0.63 mmol, 90% yield). ¹H NMR, (400 MHz,CDCl₃): 8.49 (s, 1H), 7.96 (dd, 1H), 7.71 (m, 2H), 7.53 (dd, 1H), 7.39(dd, 1H), 7.33 (d, 1H), 7.15 (m, 1H), 6.84 (br s, 1H), 6.62 (m, 1H),4.29-3.97 (br m, 4H), 3.79-3.62 (m, 3H), 3.26-2.99 (br m, 3H), 2.92-2.62(br m, 3H); MS (EI) for C₂₆H₂₃F₃IN₅O₆S: 718 (MH⁺).

To a solution of1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidin-3-01l(139.4 mg, 0.19 mmol) in DMF (1 mL) was added potassium carbonate (79mg, 0.57 mmol) and thiophenol (21 μL, 0.21 mmol). The mixture wasstirred for 45 min at room temperature then quenched with water. Theaqueous mixture was extracted twice with ethyl acetate, and the combinedorganic extracts were dried over magnesium sulfate, filtered, andconcentrated. The residue was purified by preparative reverse phase HPLCto provide1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-piperazin-2-ylazetidin-3-olas a white solid (26.8 mg, 0.05 mmol). ¹H NMR (400 MHz, CD₃OD): 7.45(dd, 1H), 7.36 (m, 1H), 7.32 (m, 1H), 7.03 (m, 1H), 6.62 (ddd, 1H), 4.51(br dd, 1H), 4.31 (br dd, 1H), 4.17-3.92 (m, 4H), 3.73-3.56 (m, 3H),3.46 (br m, 1H), 3.26 (m, 1H); MS (EI) for C₂₀H₂₀F₃IN₄O₂: 533 (MH⁺).

Example 36 1,1-Dimethylethyl{(1S)-1-[1-({4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate

To a suspension of4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylicacid (50 mg, 0.13 mmol) in DMF (2 mL), prepared using similar proceduresto those described in Reference 4, at room temperature was added1-hydroxybenzotriazole (36.3 mg, 0.27 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (52 mg, 0.27mmol) and the reaction was stirred for 2 hours. 1,1-Dimethylethyl[(1S)-1-(3-hydroxyazetidin-3-yl)ethyl]carbamate (30 mg, 0.13 mmol),prepared using procedures similar to those in Example 28, andtriethylamine (0.04 mL) were added and the mixture was stirred for 15hours. The reaction mixture was partitioned between saturated sodiumchloride and ethyl acetate. The organic layer was washed with 5% lithiumchloride solution, saturated sodium bicarbonate, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give crude productas yellow oil. The oil was purified by column chromatography (silicagel, ethyl acetate) to afford 1,1-dimethylethyl{(1S)-1-[1-({4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamateas a yellow oil (55 mg, 73% yield): ¹H NMR (400 MHz, CDCl₃): 10.24-10.23(m, 1H), 7.52-7.50 (m, 2H), 7.12-7.07 (m, 1H), 6.10-6.09 (m, 1H),5.13-5.09 (m, 1H), 4.91-4.82 (m, 1H), 4.60-4.39 (m, 2H), 4.10-4.08 (m,1H), 4.00-3.87 (m, 2H), 3.70 (d, 3H), 1.43 (s, 9H), 1.24-1.20 (m, 3H);MS (EI) for C₂₂H₂₇FIN₅O₅: 588 (MH⁺).

Using the same or analogous synthetic techniques and substituting, asnecessary, with alternative reagents, the following compounds of theinvention were prepared:

Example 36(a)

1,1-Dimethylethyl{(1S)-1-[1-({5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-1-methyl-1H-benzimidazol-6-yl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate:¹H NMR (400 MHz, CDCl₃): 7.95 (s, 1H), 7.45-7.44 (m, 1H), 7.33-7.27 (m,2H), 7.15-7.12 (m, 1H), 6.50-6.47 (m, 1H), 4.82-4.74 (m, 1H), 4.17-3.92(m, 4H), 3.86 (s, 3H), 3.74-3.60 (m, 1H), 1.40 (s, 9H), 1.11-1.06 (m,3H). MS (EI) for C₂₅H₂₈BrClFN₅O₄: 598 (MH⁺). with a chloro, bromoisotope pattern.

Example 36(b)

1,1-Dimethylethyl(2S)-2-[1-({5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-1-methyl-1H-benzimidazol-6-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate:MS (EI) for C₂₈H₃₂BrClFN₅O₄: 638 (MH⁺). with a chloro, bromo isotopepattern.

Example 376-({3-[(1S)-1-aminoethyl]-3-hydroxyazetidin-1-yl}carbonyl)-5-[(2-fluoro-4-iodophenyl)amino]-2-methylpyridazin-3(2H)-oneAcetate Salt

1,1-Dimethylethyl{(1S)-1-[1-({4-[(2-fluoro-4-iodophenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate(55 mg, 0.09 mmol), prepared using procedures similar to those describedin Example 36, was taken up in methanol (2 mL) and hydrochloric acid (4Nin dioxane, 1 mL, 4 mmol) was added and the reaction was stirred at 60°C. for 2 hours. The reaction mixture was concentrated in vacuo and waspurified by reverse-phase HPLC followed by lyophilization of the purefractions to afford6-({3-[(1S)-1-aminoethyl]-3-hydroxyazetidin-1-yl}carbonyl)-5-[(2-fluoro-4-iodophenyl)amino]-2-methylpyridazin-3(2H)-oneacetate as yellow solid (40 mg, 87%). ¹H NMR (400 MHz, CDCl₃): 10.17 (d,1H), 7.52-7.46 (m, 2H), 7.09 (t, 1H), 6.13-6.12 (m, 1H), 4.51-4.48 (m,2H), 4.18-4.03 (m, 2H), 3.73 (d, 3H), 3.35-3.28 (m, 1H), 3.22-2.80 (br,3H), 1.21-1.19 (m, 3H); MS (EI) for C₁₇H₁₉FIN₅O₃: 488 (MH⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative reagents, the following compounds of the invention wereprepared:

Example 37(a)

3-[(1S)-1-Aminoethyl]-1-({5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-1-methyl-1H-benzimidazol-6-yl}carbonyl)azetidin-3-olhydrochloride. MS (EI) for C₂₀H₂₀BrClFN₅O₂: 498 (MH⁺). with a chloro,bromo isotope pattern

Example 37(b)

1-({5-[(4-Bromo-2-chlorophenyl)amino]-4-fluoro-1-methyl-1H-benzimidazol-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-olhydrochloride. ¹H NMR (400 MHz, CD₃OD): 9.42 (s, 1H), 7.97-7.96 (m, 1H),7.57 (s, 1H), 7.30-7.27 (m, 1H), 6.70-6.66 (m, 1H), 4.60-4.55 (m, 1H),4.28 (t, 1H), 4.19 (s, 3H), 4.13-3.98 (m, 2H), 3.38-3.32 (m, 2H), 3.00(t, 1H), 1.86-1.30 (m, 6H). MS (EI) for C₂₃H₂₄BrClFN₅O₂. HCl: 538 (MH⁺).with a chloro, bromo isotope pattern

Example 381-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol

3-[(2-Fluoro-4-iodophenyl)amino]pyridine-4-carboxylic acid (200 mg,0.559 mmol), prepared using procedures similar to those described in WO2006/045514, was suspended in DMF (7 mL) and 1-hydroxybenzotriazole (151mg, 1.12 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (214 mg, 1.12 mmol) were added. The mixture was stirred atambient for 10 minutes and then triethylamine (0.078 mL, 0.559 mmol) wasadded. After a further 20 minutes, 1,1-dimethylethyl(2S)-2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate (143 mg, 0.559mmol), prepared using similar procedures to those described in Example22(a) and 22(b), and triethylamine (0.16 mL, 1.15 mmol) were added andthe mixture was stirred for 15 hours. The mixture was partitionedbetween ethyl acetate and saturated ammonium chloride. The organicportion was washed with 5% lithium chloride and twice with saturatedsodium bicarbonate, then was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography (silica gel, 60-80% ethyl acetate in hexanes) to give1,1-dimethylethyl(2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate(368 mg, 0.587 mmol, 74% yield): ¹H NMR (400 MHz, CDCl₃): 8.73 (br m,1H), 8.62 (br s, 1H), 8.14 (d, 1H), 7.47 (dd, 1H), 7.43-7.39 (m, 1H),7.20-7.12 (m, 2H), 4.38-4.21 (m, 21H), 4.16-4.01 (m, 2H), 4.01-3.88 (m,1H), 3.44-3.30 (m, 1H), 2.98-2.83 (m, 1H), 2.00-1.88 (m, 1H), 1.71-1.50(m, 6H), 1.44 (s, 9H); MS (EI) for C₂₅H₃₀FIN₄O₄: 597 (MH⁺).

1,1-Dimethylethyl(2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate(24 mg, 0.040 mmol) was dissolved in methanol (2 mL) and treated with 4N hydrochloric acid in dioxane (0.25 mL, 1 mmol) at reflux for 20minutes. The mixture was concentrated in vacuo and was purified byreverse-phase HPLC followed by lyophilization of the pure fractions toafford1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-olacetate (14 mg, 0.025 mmol, 63% yield): ¹H NMR (400 MHz, d₆-DMSO): 8.62(br s, 1H), 8.46 (s, 1H), 8.18 (dd, 1H), 7.65 (dd, 1H), 7.45 (d, 1H),7.37 (t, 1H), 7.16-7.08 (m, 1H), 4.25 (dd, 1H), 4.04 (dd, 1H), 3.90 (t,1H), 3.70 (d, 1H), 2.95 (br d, 1H), 2.52-2.42 (m, 2H), 1.78-1.68 (m,1H), 1.57 (br t, 1H), 1.47 (br d, 1H), 1.35-1.13 (m, 2H), 1.10-0.96 (m,1H); MS (EI) for C₂₀H₂₂FIN₄O₂: 497 (MH⁺).

Example 391-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol

1,1-Dimethylethyl(2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate(80 mg, 0.134 mmol), prepared using procedures similar to thosedescribed in Example 38, was dissolved in dichloromethane (3 mL) andtreated with 3-chloroperoxybenzoic acid (73% pure; 32 mg, 0.135 mmol) atambient for 7 hours. 3-chloroperoxybenzoic acid (73% pure; 32 mg, 0.135mmol) was added and the mixture was stirred for 15 hours. The mixturewas purified by column chromatography (silica gel, 0-10% ethanol inethyl acetate) to give 1,1-dimethylethyl(2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate(57 mg, 0.093 mmol, 69% yield): ¹H NMR (400 MHz, CDCl₃): 9.38 (s, 1H),8.00 (s, 1H), 7.68 (dd, 1H), 7.51 (dd, 1H), 7.46 (d, 1H), 7.19 (br d,1H), 7.09 (t, 1H), 5.78 (br, 1H), 4.44-3.98 (m, 3H), 3.98-3.87 (m, 1H),3.49-3.39 (m, 1H), 3.07-2.88 (m, 1H), 2.01-1.91 (m, 1H), 1.70-1.47 (m,6H), 1.45 (s, 9H); MS (EI) for C₂₅H₃₀FIN₄O₅: 613 (MH⁺).

1,1-Dimethylethyl(2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate(57 mg, 0.093 mmol) was dissolved in methanol (2 mL) and treated with 4Nhydrochloric acid in dioxane (0.25 mL, 1 mmol) at 50° C. for 2.25 hours.The mixture was concentrated in vacuo and was purified by reverse-phaseHPLC followed by lyophilization of the pure fractions to afford1-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-olacetate (35 mg, 0.061 mmol, 66% yield): ¹H NMR (400 MHz, d₆-DMSO): 7.83(s, 1H), 7.72 (dt, 2H), 7.55-7.51 (m, 1H), 7.47-7.41 (m, 1H), 7.24 (t,1H), 4.45-4.32 (m, 1H), 4.14-3.95 (m, 2H), 3.72 (d, 1H), 2.97 (d, 1H),2.58-2.43 (m, 2H), 1.80-1.73 (m, 1H), 1.67-1.55 (m, 1H), 1.49 (br d,1H), 1.38-1.16 (m, 2H), 1.16-1.01 (m, 1H); MS (EI) for C₂₀H₂₂FIN₄O₃: 513(MH⁺).

Example 401-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1S)-1-(methylamino)ethyl]azetidin-3-ol

To3-[(1S)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol(87.4 mg, 0.18 mmol), prepared using similar procedures to thosedescribed in Example 28, was added formaldehyde (37% aqueous, 14 mg,0.18 mmol) in methanol (2 mL) and sodium borohydride (7 mg, 0.18 mmol).The mixture was stirred for 3 h at rt, after which sodium borohydride(16 mg, 0.42 mmol) was added. Upon stirring an additional 1.25 h, moreformaldehyde (37% aqueous, 1 drop) was added, and the mixture wasstirred 3 days at rt. A further small spatula (˜50 mg) of sodiumborohydride was then added, and the mixture was stirred at rt for 30min. After quenching with 1 N HCl, the reaction mixture was purifieddirectly by preparative HPLC. The clean material was converted to itshydrochloride salt to provide1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1S)-1-(methylamino)ethyl]azetidin-3-olas a yellow solid (21.7 mg, 0.040 mmol, 22% yield). ¹H NMR (400 MHz,CD₃OD) δ 7.47 (dd, 1H), 7.36 (d, 1H), 7.31 (m, 1H), 7.06 (q, 1H), 6.62(dt, 1H), 4.36 (dd, 1H), 4.21-3.91 (m, 3H), 3.44 (q, 1H), 2.66 (s, 3H),1.29 (br m, 3H); MS (EI) for C₁₉H₁₉F₃IN₃O₂: 506 (MH⁺).

Biological Example 1 Biochemical Assay

For a biochemical measurement of MEK1 inhibitory activity, compounds ofthe invention were screened in a triple coupled cRaf-MEK-ERK2 assayusing ALPHASCREEN (Registered Trademark of Perkin Elmer) technology(Perkin Elmer). The compound of the invention, 0.5 μL of 100% DMSO stocksolution, is diluted into an assay buffer composed of 20 mM Tris(pH=7.5), 10 mM magnesium chloride, 0.03% CHAPS and 1 mM DTT.Subsequently, 10 μL of substrate mixture is added composed of unactiveMEK1(3 nM), ATP (50 μM), unactive ERK2 (4 nM), biotinylated MBP peptide(b-FFKNIVTPRTPPPSQGK, 1 μM) and antiphospho MBP peptide (0.5 nM). Themixture is then gently shaken for 30 minutes at room temperaturefollowed by addition of active cRaf (5 μL at 0.5 nM) to initiatereaction. The mixture is then shaken for 100 minutes at room temperaturethen quenched by addition of 10 μL of a mixture of 5 μg/mL stroptavidindonor beads and 5 μg/mL protein A acceptor beads in detection buffer (75mM Hepes pH=7.5, 300 mM sodium chloride, 120 mM EDTA, 0.3% BSA and 0.03%Tween), followed by incubation overnight and signal detection on anALPHAQuest® (Registered Trademark of Perkin Elmer) plate reader (PerkinElmer).

Compounds of the invention are inhibitors of MEK. The extent to whichthese compounds are MEK inhibitors can be determined by one of ordinaryskill in the art. In particular, the compounds can be tested in theassay described in Biological Example 1. When tested in that assay,certain compounds of the invention demonstrated the ability to bind toMEK. In one embodiment of the invention, the MEK inhibitor is selectedfrom the compounds in Table 1 having a MEK-binding affinity of about 4μM or less. In another embodiment, the MEK inhibitor is selected fromthe compounds in Table 1 having a MEK-binding affinity of about 3 μM orless. In another embodiment, the MEK inhibitor is selected from thecompounds in Table 1 having a MEK-binding affinity of about 2 μM orless. In another embodiment, the MEK inhibitor is selected from thecompounds in Table 1 having a MEK-binding affinity of about 1.6 μM orless. In another embodiment, the MEK inhibitor is selected from thecompounds in Table 1 having a MEK-binding affinity of about 1 μM orless. In another embodiment, the MEK inhibitor is selected from thecompounds in Table 1 having a MEK-binding affinity of about 0.7 μM orless. In another embodiment, the MEK inhibitor is selected from thecompounds in Table 1 having a MEK-binding affinity of about 0.3 μM orless. In another embodiment, the MEK inhibitor is selected from thecompounds in Table 1 having a MEK-binding affinity of about 0.2 μM orless. In another embodiment, the MEK inhibitor is selected from thecompounds in Table 1 having a MEK-binding affinity of about 0.1 μM orless. In another embodiment, the MEK inhibitor is selected from thecompounds in Table 1 having a MEK-binding affinity of about 0.05 μM orless.

Biological Example 2 Endogenous ERK Phosphorylation ELISA Assay

MDA-MB-231T (ATCC), Calu-6 (ATCC), HCT 116 (ATCC), A2058 (ATCC), andA375 (ATCC) cells were seeded at 20000, 30000, 30000, 20000, and 30000cells/well, respectively, onto black 96-well microtiter plates (Costar3904), in DMEM (Cellgro) containing 10% FBS (Heat-Inactivated, Cellgro),1% NEAA (Cellgro), and 1% Pen/Strep (Cellgro). SK-MEL-28 (ATCC) cellswere seeded at 20000 cells/well in MEM (ATCC) containing 10% FBS(Heat-Inactivated, Cellgro), and 1% Pen/Strep (Cellgro). The cells werethen incubated at 37° C., 5% CO₂ for 24 h. Serum starvation wasperformed by replacing the medium with serum-free DMEM or MEM for anadditional 24 h. Serial dilutions of test compounds in fresh serum-freemedium in a final concentration of 0.3% DMSO (vehicle) were added to thecells and incubated for 1 h. Negative control wells were in serum-freemedium+0.3% DMSO only. After treatment, the medium was removed and cellswere fixed with 4% formaldehyde, followed by quenching of endogenousperoxidases with 0.6% H₂O₂. Plates were then blocked (10% FIBS, Cellgro)and incubated with mouse monoclonal anti-phospho-p44/42 MAPK, E10(1:2000, Cell Signaling), followed by secondary antibody(HRP-conjugated, goat anti-mouse IgG, 1:3000 from Jackson ImmunoResearchLaboratories, Inc). Washing of the plates was performed with PBS-T (0.1%Triton X-100) in between all incubation steps. A luminol-based substratesolution was then added and plates read using the Victor Wallac machine.IC₅₀ values were determined based on total ERK phosphorylation withcompound treatment versus total ERK phosphorylation with 0.3% DMSOtreatment alone.

Biological Example 3 BrdU Cell Proliferation Assay

MDA-MB-231T (ATCC), Calu-6 (ATCC), HCT 116 (ATCC), A2058 (ATCC), A375(ATCC), and Colo-205 (ATCC) cells were plated at densities of 2500,3500, 3500, 2500, 3500, and 15000 cells/well onto 96-well microtiterplates (Cat#3904, Costar), in DMEM (Cellgro) containing 10% FBS (HeatInactivated, Cellgro), 1% Pen/Strep (Cellgro), and 1% NEAA (Cellgro). SKMEL-28 (ATCC) and WM-266-4 (ATCC) were plated at densities of 2000 and6000 cells/well in MEM (ATCC) containing 10% FBS (Heat-Inactivated,Cellgro), and 1% Pen/Strep (Cellgro). The cells were incubated overnightat 37° C., 5% CO₂ for 18 h. The next day, cells were treated with aserial dilution of compound in medium (containing a final concentrationof 0.3% DMSO). Triplicate wells were used for each compoundconcentration. The control wells received 0.3% DMSO media. The cultureswere incubated at 37° C., 5% CO₂ for an additional 48 h. The cells wereassayed for proliferation according to the “Cell Proliferation ELISA,Bromo Deoxyuridine (BrdU) (chemiluminescence) kit” from Roche. The cellswere treated with the BrdU labeling solution and then fixed withFixDenat solution. Anti-BrdU-POD (PerOxiDase) conjugate was added to thecells, after which the plates were washed 3× with 1×PBS. Substratesolution was added, and the plates were read for luminescence using theVictor Wallac machine. IC₅₀ values were calculated based on the cellproliferation with compound treatment compared to the vehicle control.

Biological Example 4 In Vivo Mouse Models

Female athymic nude mice (NCr) 5-8 weeks of age and weighingapproximately 20 g were purchased from Taconic (Germantown, N.Y.). Priorto initiation of a study, the animals were allowed to acclimate for aminimum of 48 h. During these studies, animals were provided food andwater ad libitum and housed in a room conditioned at 70-75° F. and 60%relative humidity. A 12 h light and 12 h dark cycle was maintained withautomatic timers.

J Colo-205 human colorectal carcinoma cells were cultured in vitro inDMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone),Penicillin-Streptomycin and non-essential amino acids at 37° C. in ahumidified, 5% CO₂ atmosphere. On day 0, cells were harvested bytrypsinization, and 3×10⁶ cells (passage #3, 92% viability) in 0.1 mlice-cold Hank's balanced salt solution were implanted intradermally inthe hind-flank of 5-8 week old female athymic nude mice.

A375 human melanoma cells were cultured in vitro in DMEM (Mediatech)supplemented with 10% Fetal Bovine Serum (Hyclone),Penicillin-Streptomycin and non-essential amino acids at 37° C. in ahumidified, 5% CO₂ atmosphere. On day 0, cells were harvested bytrypsinization, and 5×10⁶ cells (passage #8, >99% viability) in 0.1 mLice-cold Hank's balanced salt solution were implanted intradermally inthe hind-flank of 5-8 week old female athymic nude mice.

A2058 human melanoma cells were cultured in vitro in DMEM (Mediatech)supplemented with 10% Fetal Bovine Serum (Hyclone),Penicillin-Streptomycin and non-essential amino acids at 37° C. in ahumidified, 5% CO₂ atmosphere. On day 0, cells were harvested bytrypsinization, and 3×10⁶ cells (passage #5, 80% viability) in 0.1 mLice-cold Hank's balanced salt solution were implanted intradermally inthe hind-flank of 5-8 week old female athymic nude mice.

MDA-MB-231 human breast adenocarcinoma cells were cultured in vitro inDMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone),Penicillin-Streptomycin and non-essential amino acids at 37° C. in ahumidified, 5% CO₂ atmosphere. On day 0, cells were harvested bytrypsinization, and 1×10⁶ cells (passage #6, >99% viability) in 0.1 mLice-cold Hank's balanced salt solution were implanted subcutaneouslyinto the mammary fat pad of 5-8 week old female athymic nude mice.

Calu-6 human lung anaplastic carcinoma cells were cultured in vitro inDMEM (Mediatech) supplemented with 10% Fetal Bovine Serum (Hyclone),Penicillin-Streptomycin and non-essential amino acids at 37° C. in ahumidified, 5% CO₂ atmosphere. On day 0, cells were harvested bytrypsinization, and 5×10⁶ cells (passage #8, 96% viability) in 0.1 mLice-cold Hank's balanced salt solution were implanted intradermally inthe hind-flank of 5-8 week old female athymic nude mice.

For subcutaneous or intradermal tumors, the mean tumor weight of eachanimal in the respective control and treatment groups was determinedtwice weekly during the study. Tumor weight (TW) was determined bymeasuring perpendicular diameters with a caliper, using the followingformula: tumor weight (mg)=[tumor volume=length (mm)×width² (mm²)]/2.

Percent inhibition of tumor growth (TGI) is determined with thefollowing formula:

$\left( {1 - \left( \frac{\left( {X_{f} - X_{0}} \right)}{\left( {Y_{f} - X_{0}} \right)} \right)} \right)*100$

where X₀=average TW of all tumors on group day; X_(f)=TW of treatedgroup on Day f; Y_(f)=TW of vehicle control group on Day f

If tumors regress below their starting sizes, then the percent tumorregression is determined with the following formula:

$\left( \frac{\left( {X_{0} - {Xf}} \right)}{X_{0}} \right)*100$

TGI is calculated individually for each tumor to obtain a mean±SEM valuefor each experimental group. Statistical significance is determinedusing the 2-tailed Student's t-test (significance defined as P<0.05).

Pharmaceutical Composition Examples

The following are representative pharmaceutical formulations containinga compound of Formula I.

Tablet Formulation

The following ingredients are mixed intimately and pressed into singlescored tablets.

Ingredient Quantity per tablet, mg compound of this invention 400Cornstarch 50 croscarmellose sodium 25 Lactose 120 magnesium stearate 5

Capsule Formulation

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Ingredient Quantity per tablet, mg compound of this invention 200lactose, spray-dried 148 magnesium stearate 2

Suspension Formulation

The following ingredients are mixed to form a suspension for oraladministration.

Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 gsodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 ggranulated sugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K(Vanderbilt Co.) 1.0 g Flavoring 0.035 mL Colorings 0.5 mg distilledwater q.s. to 100 mL

Injectable Formulation

The following ingredients are mixed to form an injectable formulation.

Ingredient Amount compound of this invention 1.2 g sodium acetate buffersolution 0.4M 2.0 mL HCl (1N) or NaOH (1M) q.s. to suitable pH water(distilled, sterile) q.s.to 20 mL

All of the above ingredients, except water, are combined and heated to60-70.degree. C. with stirring. A sufficient quantity of water at60.degree. C. is then added with vigorous stirring to emulsify theingredients, and water then added q.s. to 100 g.

Suppository Formulation

A suppository of total weight 2.5 g is prepared by mixing the compoundof the invention with Witepsol® H-15 (triglycerides of saturatedvegetable fatty acid; Riches-Nelson, Inc., New York), and has thefollowing composition:

Ingredient Quantity per tablet, mg compound of this invention 500Witepsol ® H-15 balance

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Theinvention has been described with reference to various specificembodiments and techniques. However, it should be understood that manyvariations and modifications may be made while remaining within thespirit and scope of the invention. It will be obvious to one of skill inthe art that changes and modifications may be practiced within the scopeof the appended claims. Therefore, it is to be understood that the abovedescription is intended to be illustrative and not restrictive. Allpatents, patent applications and publications cited in this applicationare hereby incorporated by reference in their entirety for all purposesto the same extent as if each individual patent, patent application orpublication were so individually denoted.

We claim:
 1. A compound of formula I:

or a pharmaceutically acceptable salt or solvate, thereof, wherein A, X,R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined in Group A, Group B, GroupC, or Group D: Group A: A is arylene optionally substituted with one,two, three or four groups selected from R¹⁰, R¹², R¹⁴, R¹⁶, and R¹⁹where R¹¹, R¹², R¹⁴ and R¹⁶ are independently hydrogen, alkyl, alkenyl,alkynyl, halo, haloalkoxy, hydroxy, alkoxy, amino, alkylamino,dialkylamino, haloalkyl, —NHS(O)₂R⁸, —CN, —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁸R^(8′) and —NR⁸C(O)R^(8′) and where R¹⁹ is hydrogen, alkyl, oralkenyl; X is alkyl, halo, haloalkyl, or haloalkoxy; R¹, R², R³, R⁴, R⁵and R⁶ are independently hydrogen, halo, nitro, —NR⁸R^(8′), —OR⁸,—NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′),—NR⁸C(O)R^(8′), —CH₂N(R²⁵)(NR^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)),—CH₂NR²⁵SC(═NH)(N(R^(25a))(CN)), —CH₂NR²⁵C(═NH)(R²⁵),—CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl, cycloalkyl,heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl,cycloalkyl, heteroaryl, and heterocycloalkyl are independentlyoptionally substituted with one, two, three, four, five, six or sevengroups independently selected from halo, alkyl, haloalkyl, nitro,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, —OR⁸, —NR⁸R^(8′),—NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),—NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or one of R¹and R² together with the carbon to which they are attached, R³ and R⁴together with the carbon to which they are attached, and R⁵ and R⁶together with the carbon to which they are attached form C(O) orC(═NOH); m is 0, 1, or 2; R⁷ is hydrogen, halo or alkyl; R⁸, R^(8′) andR^(8″) are independently selected from hydrogen, hydroxy, optionallysubstituted alkoxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heteroaryl, and heterocycloalkyl; where the alkyl, alkenyl, alkynyl,aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independentlyoptionally substituted with one, two three, four, or five groupsindependently selected from alkyl, halo, hydroxy, hydroxyalkyl,optionally substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy,alkoxycarbonyl, alkenyloxycarbonyl, optionally substituted cycloalkyl,optionally substituted cycloalkyloxycarbonyl, optionally substitutedaryl, optionally substituted aryloxy, optionally substitutedaryloxycarbonyl, optionally substituted arylalkyl, optionallysubstituted arylalkyloxy, optionally substituted arylalkyloxycarbonyl,nitro, cyano, optionally substituted heterocycloalkyl, optionallysubstituted heteroaryl, —S(O)_(n)R³¹ (where n is 0, 1, or 2 and R³¹ isoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted heterocycloalkyl, or optionally substituted heteroaryl),—NR³⁴SO₂R^(34a) (where R³⁴ is hydrogen or alkyl and R^(34a) is alkyl,alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl),—SO₂NR³⁵R^(35a) (where R³⁵ is hydrogen or alkyl and R^(35a) is alkyl,alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl),—NR³²C(O)R^(32a) (where R³² is hydrogen or alkyl and R^(32a) is alkyl,alkenyl, alkoxy, or cycloalkyl), —NR³⁰R^(30′) (where R³⁰ and R^(30′) arindependently hydrogen, alkyl, or hydroxyalkyl), and —C(O)NR³³R^(33a)(where R is hydrogen or alkyl and R^(33a) is alkyl, alkenyl, alkynyl, orcycloalkyl); and R⁹ is alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heteroaryl, and heterocycloalkyl; where the alkyl, alkenyl, alkynyl,aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independentlyoptionally substituted with one, two, three, four, or five groupsselected from halo, hydroxy, alkyl, haloalkyl, haloalkoxy, amino,alkylamino, and dialkylamino; Group B: A is heteroarylene optionallysubstituted with one, two, three, or four groups selected from R¹⁰, R¹²,R¹⁴, R¹⁶ and R¹⁹ where R¹⁰, R¹², R¹⁴ and R¹⁶ are independently hydrogen,alkyl, alkenyl, alkynyl, halo, haloalkoxy, hydroxy, alkoxy, cyano,amino, alkylamino, dialkylamino, haloalkyl, alkylsulfonylamino,alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, alkenyloxycarbonyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, oralkylcarbonylamino; where R¹⁹ is hydrogen, alkyl, or alkenyl; and whereeach alkyl and alkenyl, either alone or as part of another group withinR¹⁰, R¹², R¹⁴, R¹⁶, and R¹⁹, is independently optionally substitutedwith halo, hydroxy, or alkoxy; X is alkyl, halo, haloalkyl, orhaloalkoxy; R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen, halo,nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′),—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),—NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),—CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵SC(═NH)(N(R^(25a))(CN)),—CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl,alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl areindependently optionally substituted with one, two, three, four, five,six or seven groups independently selected from halo, alkyl, haloalkyl,nitro, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, —OR⁸, —NR⁸R^(8′),—NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),—NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or one of R¹and R² together with the carbon to which they are attached, R³ and R⁴together with the carbon to which they are attached, and R⁵ and R⁶together with the carbon to which they are attached form C(O) orC(═NOH); m is 1 or 2; R⁷ is hydrogen, halo or alkyl; and R⁸, R^(8′) andR^(8″) are independently selected from hydrogen, hydroxy, optionallysubstituted alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,cycloalkyl, heteroaryl, and heterocycloalkyl, where the alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl areindependently optionally substituted with one, two three, four, or fivegroups independently selected from alkyl, halo, hydroxy, hydroxyalkyl,optionally substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, carboxyester, nitro, cyano, —S(O)_(n)R³¹ (where n is 0, 1, or 2 and R³¹ isoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl, oroptionally substituted heteroaryl), —NR³⁶S(O)₂R^(36a) (where R³⁶ ishydrogen, alkyl, or alkenyl and R^(36a) is alkyl, alkenyl, optionallysubstituted aryl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, or optionally substituted heteroaryl),—S(O)₂NR³⁷R^(37a) (where R³⁷ is hydrogen, alkyl, or alkenyl and R^(37a)is alkyl, alkenyl, optionally substituted aryl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, or optionallysubstituted heteroaryl), optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted arylalkyl, optionally substituted aryloxy, optionallysubstituted arylalkyloxy, optionally substituted heteroaryl, —NHC(O)R³²(where R³² is alkyl, alkenyl, alkoxy, or cycloalkyl) and —NR³⁰R^(30′)(where R³⁰ and R^(30′) are independently hydrogen, alkyl, orhydroxyalkyl), and —C(O)NHR³³ (where R³³ is alkyl, alkenyl, alkynyl, orcycloalkyl); Group C: A is

where R¹⁰ is hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkoxy,hydroxy, alkoxy, amino, alkylamino, dialkylamino, haloalkyl, —NHS(O)₂R⁸,—CN, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′) and —NR⁸C(O)R^(8′); R^(10a) ishydrogen, alkyl, or alkenyl; Y¹ is ═CH— or ═N—; X is alkyl, halo,haloalkyl, or haloalkoxy; R¹, R², R³, R⁴, R⁵ and R⁶ are independentlyhydrogen, halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸,—S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),—NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),—CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵SC(═NH)(N(R^(25a))(CN)),—CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl,alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl areindependently optionally substituted with one, two, three, four, five,six or seven groups independently selected from halo, alkyl, haloalkyl,nitro, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, —OR⁸, —NR⁸R^(8′),—NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),—NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or one of R¹and R² together with the carbon to which they are attached, R³ and R⁴together with the carbon to which they are attached, and R⁵ and R⁶together with the carbon to which they are attached form C(O) orC(═NOH); m is 1 or 2; R⁷ is hydrogen, halo or alkyl; and R⁸, R^(8′) andR_(8″) are independently selected from hydrogen, hydroxy, optionallysubstituted alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,cycloalkyl, heteroaryl, and heterocycloalkyl, where the alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl areindependently optionally substituted with one, two three, four, or fivegroups independently selected from alkyl, halo, hydroxy, hydroxyalkyl,optionally substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, carboxyester, nitro, cyano, —S(O)_(n)R³¹ (where n is 0, 1, or 2 and R³¹ isoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl, oroptionally substituted heteroaryl), —NR³⁶S(O)₂R^(36a) (where R³⁶ ishydrogen, alkyl, or alkenyl and R^(36a) is alkyl, alkenyl, optionallysubstituted aryl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, or optionally substituted heteroaryl),—S(O)₂NR³⁷R^(37a) (where R³⁷ is hydrogen, alkyl, or alkenyl and R^(37a)is alkyl, alkenyl, optionally substituted aryl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, or optionallysubstituted heteroaryl), optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted arylalkyl, optionally substituted aryloxy, optionallysubstituted arylalkyloxy, optionally substituted heteroaryl, —NHC(O)R³²(where R³² is alkyl, alkenyl, alkoxy, or cycloalkyl) and —NR³⁰R^(30′)(where R³⁰ and R^(30′) are independently hydrogen, alkyl, orhydroxyalkyl), and —C(O)NHR³³ (where R³³ is alkyl, alkenyl, alkynyl, orcycloalkyl); or Group D: A is

R⁴⁰ and R^(40a) are independently hydrogen or alkyl; X is alkyl, halo,haloalkyl, or haloalkoxy; R¹, R², R³, R⁴, R⁵ and R⁶ are independentlyhydrogen, halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸,—S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),—NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),—CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵SC(═NH)(N(R^(25a))(CN)),—CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl,alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl areindependently optionally substituted with one, two, three, four, five,six or seven groups independently selected from halo, alkyl, haloalkyl,nitro, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, —OR⁸, —NR⁸R^(8′),—NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),—NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or one of R¹and R² together with the carbon to which they are attached, R³ and R⁴together with the carbon to which they are attached, and R⁵ and R⁶together with the carbon to which they are attached form C(O) orC(═NOH); m is 1 or 2; R⁷ is hydrogen, halo or alkyl; and R⁸, R^(8′) andR_(8″) are independently selected from hydrogen, hydroxy, optionallysubstituted alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl,cycloalkyl, heteroaryl, and heterocycloalkyl, where the alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl areindependently optionally substituted with one, two three, four, or fivegroups independently selected from alkyl, halo, hydroxy, hydroxyalkyl,optionally substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, carboxyester, nitro, cyano, —S(O)_(n)R³¹ (where n is 0, 1, or 2 and R³¹ isoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl, oroptionally substituted heteroaryl), —NR³⁶S(O)₂R^(36a) (where R³⁶ ishydrogen, alkyl, or alkenyl and R^(36a) is alkyl, alkenyl, optionallysubstituted aryl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, or optionally substituted heteroaryl),—S(O)₂NR³⁷R^(37a) (where R³⁷ is hydrogen, alkyl, or alkenyl and R^(37a)is alkyl, alkenyl, optionally substituted aryl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, or optionallysubstituted heteroaryl), optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted arylalkyl, optionally substituted aryloxy, optionallysubstituted arylalkyloxy, optionally substituted heteroaryl, —NHC(O)R³²(where R³² is alkyl, alkenyl, alkoxy, or cycloalkyl) and —NR³⁰R^(30′)(where R³⁰ and R^(30′) are independently hydrogen, alkyl, orhydroxyalkyl), and —C(O)NHR″ (where R³³ is alkyl, alkenyl, alkynyl, orcycloalkyl).
 2. The Compound of claim 1 selected from Group A, Group B,and Group C where Group A A is phenylene optionally substituted with oneor two groups selected from R¹⁰, R¹², R¹⁴, and R¹⁶ where R¹⁰, R¹², R¹⁴and R¹⁶ are independently hydrogen or halo; X is halo; R¹, R², R⁵ and R⁶are hydrogen; R³ is hydrogen, halo, hydroxy, alkoxy, or amino; R⁴ ishydrogen, —NR⁸R^(8′), —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),—CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN)),—CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl,cycloalkyl, heterocycloalkyl, or heteroaryl; where the alkyl isoptionally substituted with one, two, or three groups independentlyselected from —OR⁸, halo, nitro, —S(O)_(m)R⁹, optionally substitutedheterocycloalkyl, —NR⁸R^(8′), —NR⁸C(O)R^(8′), —NR⁸S(O)₂R⁹,—NR⁸C(O)OR^(8′), and aryl; where the cycloalkyl is optionallysubstituted with one or two groups selected from —OR⁸ and —NR⁸R^(8′);where the heterocycloalkyl is optionally substituted with one or twogroups independently selected from alkyl and —C(O)OR⁸; and where theheteroaryl is optionally substituted with —NR⁸R^(8′); or R³ and R⁴together with the carbon to which they are attached form C(O) orC(═NOH); m is 0; R⁷ is halo; R⁸ and R^(8′) are independently selectedfrom hydrogen, hydroxy, alkyl, alkenyl, alkynyl, aryl, heterocycloalkyl,heteroaryl, and cycloalkyl; where the R⁸ and R^(8′) alkyl areindependently optionally substituted with one, two, or three groupsindependently selected from hydroxy, —NR³⁰R^(30′) (where R³⁰ and R^(30′)are independently hydrogen, alkyl, or hydroxyalkyl), optionallysubstituted heteroaryl, optionally substituted cycloalkyl), optionallysubstituted alkoxy, optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted heterocycloalkyl, optionallysubstituted heteroaryl, —C(O)NR³³R^(33a) (where R³³ is hydrogen or alkyland R^(33a) is alkyl, alkenyl, alkynyl, or cycloalkyl), optionallysubstituted aryloxy, —S(O)_(n)R³¹ (where n is 0 and R³¹ is alkyl),carboxy, alkoxycarbonyl, and —NR³²C(O)R^(32a) (where R³² is hydrogen oralkyl and R^(32a) is alkyl, alkenyl, alkoxy, or cycloalkyl); or wherethe alkyl is optionally substituted with one, two, three, four, or fivehalo; where the R⁸ and R^(8′) heteroaryl are independently optionallysubstituted with one or two groups independently selected from amino andalkyl; where the R⁸ and R^(8′) heterocycloalkyl are independentlyoptionally substituted with one, two, or three groups independentlyselected from alkyl, alkoxycarbonyl, optionally substituted arylalkyl,hydroxy, alkoxy, and hydroxyalkyl; where the R⁸ and R^(8′) aryl areindependently optionally substituted with one or two groupsindependently selected from hydroxy, alkoxy, halo, —NR³²C(O)R^(32a)(where R³² is hydrogen or alkyl and R^(32a) is alkyl, alkenyl, alkoxy,or cycloalkyl), and —NR³⁴SO₂R^(34a) (where R³⁴ is hydrogen or alkyl andR^(34a) is alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, orheterocycloalkyl); and where the R⁸ and R^(8′) cycloalkyl areindependently optionally substituted with one, two, or three groupsindependently selected from hydroxy, hydroxyalkyl, alkoxy, carboxy,—C(O)NR³³R^(33a) (where R³³ is hydrogen or alkyl and R^(33a) is alkyl,alkenyl, alkynyl, or cycloalkyl), and optionally substituted cycloalkyl;and R⁹ is alkyl or aryl; Group B A is thien-3,4-diyl,benzo[d]isoxazol-5,6-diyl, 1H-indazol-5,6-diyl (optionally substitutedat the N1 position with R¹⁹ where R¹⁹ is alkyl or alkenyl),benzo[d]oxazol-5,6-diyl, 1H-benzo[d]imidazol-5,6-diyl (optionallysubstituted at the N1 position with R¹⁹ where R¹⁹ is alkyl or alkenyl),1H-benzo[d][1,2,3]triazol-5,6-diyl (optionally substituted at the N1position with R¹⁹ where R¹⁹ is alkyl or alkenyl),imidazo[1,2-a]pyridin-6,7-diyl, cinnolin-6,7-diyl, quinolin-6,7-diyl,pyridin-3,4-diyl, 1-oxido-pyridin-3,4-diyl,[1,2,4]triazolo[4,3-a]pyridin-6,7-diyl, or2,3-dihydroimidazo[1,2-a]pyridin-6,7-diyl; where A is optionallysubstituted with one, two, or three groups independently selected fromR¹⁰, R¹², R¹⁴, R¹⁶ and R¹⁹ where R¹⁰, R¹², R¹⁴ and R¹⁶ are independentlyhydrogen, alkyl, halo, or amino; and R¹⁹ is hydrogen or alkyl; X ishalo; R¹, R², R⁵ and R⁶ are hydrogen; R³ is hydrogen or hydroxy; R⁴ is—NR⁸R^(8′), heterocycloalkyl, heteroaryl, or alkyl; where the alkyl isoptionally substituted with —NR⁸R^(8′) and where the heteroaryl isoptionally substituted with alkyl; R⁷ is halo; R⁸ is hydrogen or alkyl;and R^(8′) is hydrogen, alkyl, or cycloalkyl; where the cycloalkyl isoptionally substituted with one or two groups independently selectedfrom hydroxy and alkyl; Group C A is

R¹⁰ is hydrogen or halo; R¹¹ is hydrogen or alkyl; Y¹ is —CH— or —N—; Xis halo; R¹, R², R⁵ and R⁶ are hydrogen; R³ is hydrogen or hydroxy; R⁴is —NR⁸R^(8′), heterocycloalkyl, heteroaryl, or alkyl; where the alkylis optionally substituted with —NR⁸R^(8′) and where the heteroaryl isoptionally substituted with alkyl; R⁷ is halo; R⁸ is hydrogen or alkyl;and R^(8′) is hydrogen, alkyl, or cycloalkyl; where the cycloalkyl isoptionally substituted with one or two groups independently selectedfrom hydroxy and alkyl.
 3. The compound of claim 1 where R³ is halo,nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′),—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),—NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),—CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN)),—CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl,alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl areindependently optionally substituted with one, two, three, four, five,six or seven groups independently selected from halo, alkyl, haloalkyl,nitro, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″),—NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); and R⁴ is as defined in claim 1; orR³ and R⁴ together with the carbon to which they are attached form C(O)or C(═NOH).
 4. The compound of claim 1 where R³ and R⁴ are independentlyhalo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸,—S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),—NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),—CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵SC(═NH)(N(R^(25a))(CN)),—CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl,alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the alkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl areindependently optionally substituted with one, two, three, four, five,six or seven groups independently selected from halo, alkyl, haloalkyl,nitro, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″),—NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or R³ and R⁴ together with thecarbon to which they are attached form C(O) or C(═NOH).
 5. The compoundaccording to claim 1 wherein R⁷ is halo.
 6. The compound according toclaim 1 wherein X is halo.
 7. The compound according to claim 1 whereinR¹, R², R⁵, and R⁶ are hydrogen.
 8. The compound of claim 1 selectedfrom Group A where A is phenylene; and R⁴ is —NR⁸R^(8′) (where R⁸ ishydrogen, hydroxy, alkyl, alkoxy, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl and R^(8′) is hydroxy, alkoxy, aryl, cycloalkyl,heteroaryl, or heterocycloalkyl), —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸,—S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),—NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),—CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵SC(═NH)(N(R^(25a))(CN)),—CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkenyl, oralkynyl; where the alkenyl and alkynyl are optionally substituted withone, two, three, four, five, six or seven groups independently selectedfrom halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted arylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹,—CN, —S(O)_(m)R⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),—NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or R³ and R⁴together with the carbon to which they are attached form C(O) orC(═NOH).
 9. The compound of claim 1 where R³ is hydrogen, halo, hydroxy,amino, or alkoxy.
 10. The compound of claim 1 where R⁴ is hydrogen,—NR⁸R^(8′), —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),—CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN)),—CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl,cycloalkyl, heterocycloalkyl, or heteroaryl; where the alkyl isoptionally substituted with one, two, or three —OR⁸, halo, nitro,—S(O)_(m)R⁹, optionally substituted heterocycloalkyl, —NR⁸R^(8′),—NR⁸C(O)R^(8′), —NR⁸S(O)₂R⁹, —NR⁸C(O)OR^(8′), aryl; where the cycloalkylis optionally substituted with one or two —NR⁸R^(8′); where theheterocycloalkyl is optionally substituted with one or two groupsindependently selected from alkyl and —C(O)OR⁸; and where the heteroarylis optionally substituted with —NR⁸R^(8′).
 11. The compound of claim 1selected from Group A where A is phenylene optionally substituted withone or two groups independently selected from R¹⁰, R¹², R¹⁴, and R¹⁶where R¹⁰, R¹², R¹⁴ and R¹⁶ are independently hydrogen or halo.
 12. Thecompound of claim 1 selected from Group A where A is phenylene; R³ ishydrogen; and R⁴ is hydrogen, —NR⁸R^(8′), —C(O)NR⁸R^(8′),—NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), alkyl, or heterocycloalkyl; where thealkyl is optionally substituted with one or two groups independentlyselected from —OR⁸ and —NR⁸R^(8′); and where the heterocycloalkyl isoptionally substituted with —NR⁸R^(8′).
 13. The compound of claim 1selected from Group A where A is phenylene; R³ is alkoxy; and R⁴ isalkyl or heterocycloalkyl where the alkyl is substituted with—NR⁸R^(8′).
 14. The compound of claim 1 selected from Group A where A isphenylene; R³ is halo; and R⁴ is alkyl or heterocycloalkyl where thealkyl is substituted with —NR⁸R^(8′).
 15. The compound of claim 1selected from Group A where A is phenylene and R³ and R⁴ together withthe carbon to which they are attached form C(O) or C(═NOH).
 16. Thecompound of claim 1 selected from Group A where A is phenylene; R³ ishydroxy; and R⁴ is hydrogen, —C(O)NR⁸R^(8′),—CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN)),—CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl,heterocycloalkyl, cycloalkyl, heterocycloalkyl, or heteroaryl; where thealkyl is optionally substituted with one, two, or three groups selectedfrom —OR⁸, halo, nitro, —S(O)_(m)R⁹, optionally substitutedheterocycloalkyl, —NR⁸R^(8′), —NR⁸C(O)R^(8′), optionally substitutedheteroaryl, —NR⁸S(O)₂R⁹, —NR⁸C(O)OR^(8′), and aryl; where the cycloalkylis optionally substituted with one or two groups independently selectedfrom —NR⁸R^(8′) and —C(O)NR³³R^(33a); where the heterocycloalkyl isoptionally substituted with one, two or three groups independentlyselected from alkyl and —C(O)OR⁸; and where the heteroaryl is optionallysubstituted with —NR⁸R^(8′).
 17. The compound of claim 1 selected fromGroup A where A is phenylene; R⁷ is iodo or bromo; X is fluoro orchloro; and R¹, R², R⁵, and R⁶ are hydrogen; and R¹⁰, R¹², R¹⁴, and R¹⁶are independently hydrogen or fluoro.
 18. The compound of claim 17 whereR¹⁰ is 3-fluoro and R¹², R¹⁴, and R¹⁶ are hydrogen or halo; R¹⁰ is3-fluoro, R¹² is 4-fluoro, and R¹⁴ and R¹⁶ are hydrogen; R¹⁰ is4-fluoro, R¹² is 5-fluoro, and R¹⁴ and R¹⁶ are hydrogen; R¹⁰ is4-fluoro, R¹² is 6-fluoro, and R¹⁴ and R¹⁶ are hydrogen; or R¹² is4-fluoro and R¹⁰, R¹⁴, and R¹⁶ are hydrogen.
 19. The Compound of claim 1selected from Group A where A is phenylene and R³ is hydroxy.
 20. TheCompound of claim 19 where R⁴ is —C(O)NR⁸R^(8′),—CH₂N(R²⁵)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)), —CH₂NR²⁵C(═NH)(N(R^(25a))(CN)),—CH₂NR²⁵C(═NH)(R²⁵), —CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl,cycloalkyl, heterocycloalkyl, or heteroaryl; where the alkyl,cycloalkyl, heteroaryl, and heterocycloalkyl are independentlyoptionally substituted with one, two, three, or four groupsindependently selected from halo, alkyl, haloalkyl, nitro, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, optionally substituted arylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′)and —NR⁸C(O)R^(8′); or where the alkyl is optionally substituted withone, two, three, four, five, six or seven halo.
 21. The Compound ofclaim 20 where R⁴ is alkyl, heterocycloalkyl, or heteroaryl; where thealkyl is optionally substituted with —NR⁸R^(8′); where theheterocycloalkyl is optionally substituted with alkyl or —C(O)OR⁸; andwhere the heteroaryl is optionally substituted with alkyl.
 22. TheCompound of claim 1 where R¹ is halo, nitro, nitro, —NR⁸R^(8′), —OR⁸,—NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′),—NR⁸C(O)R^(8′), —CH₂N(R²⁵)(NR^(25a)R^(25b)),—CH₂NR²⁵C(═NH)(NR^(25a)R^(25b)), —CH₂NR²⁵C(═NH)(N(R^(25a))(NO₂)),—CH₂NR²⁵SC(═NH)(N(R^(25a))(CN)), —CH₂NR²⁵C(═NH)(R²⁵),—CH₂NR²⁵C(NR^(25a)R^(25b))═CH(NO₂), alkyl, alkenyl, alkynyl, cycloalkyl,heteroaryl, or heterocycloalkyl; where the alkyl, alkenyl, alkynyl,cycloalkyl, heteroaryl, or heterocycloalkyl are independently optionallysubstituted with one, two, three, four, five, six or seven groupsindependently selected from halo, alkyl, haloalkyl, nitro, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, optionally substituted arylalkyl,optionally substituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN,—S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′)—NR⁸C(O)NR^(8′)R^(8″),—NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); R³ is hydroxy; and R⁴ isheterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionallysubstituted with —NR⁸R^(8′) and where the heteroaryl is optionallysubstituted with alkyl.
 23. The Compound of claim 1 selected from GroupB where A is thien-3,4-diyl, benzo[d]isoxazol-5,6-diyl,1H-indazol-5,6-diyl (optionally substituted at the N1 position with R¹⁹where R¹⁹ is alkyl or alkenyl), benzo[d]oxazol-5,6-diyl,1H-benzo[d]imidazol-5,6-diyl (optionally substituted at the N1 positionwith R¹⁹ where R¹⁹ is alkyl or alkenyl),1H-benzo[d][1,23]triazol-5,6-diyl (optionally substituted at the N1position with R¹⁹ where R¹⁹ is alkyl or alkenyl),imidazo[1,2-a]pyridin-6,7-diyl, cinnolin-6,7-diyl, quinolin-6,7-diyl,pyridin-3,4-diyl, 1-oxido-pyridin-3,4-diyl,[1,2,4]triazolo[4,3-a]pyridin-6,7-diyl, or2,3-dihydroimidazo[1,2-a]pyridin-6,7-diyl.
 24. The Compound of claim 1where A is thien-3,4-diyl; R¹⁰ and R¹² are hydrogen; X and R⁷ are halo;and R¹, R², R⁵, and R⁶ are hydrogen.
 25. The Compound of claim 24 whereR³ is hydrogen or hydroxy; and R⁴ is —NR⁸R^(8′), heterocycloalkyl,heteroaryl, or alkyl, where the alkyl is optionally substituted with—NR⁸R^(8′).
 26. The Compound of claim 1 selected from Group B where A isbenzo[d]isoxazol-5,6-diyl; R¹⁰, R¹², and R¹⁴ are independently hydrogen,halo, or alkyl; R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³is hydroxy; and R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where thealkyl is optionally substituted with —NR⁸R^(8′) and where the heteroarylis optionally substituted with alkyl.
 27. The Compound of claim 23according to Formula I(g) or I(h):

where R¹⁰, R¹², and R¹⁴ are independently hydrogen, halo, or alkyl; R¹⁹is alkyl or alkenyl; R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo;R³ is hydroxy; and R⁴ is heterocycloalkyl, alkyl, or heteroaryl, wherethe alkyl is optionally substituted with —NR⁸R^(8′) and where theheteroaryl is optionally substituted with alkyl.
 28. The Compound ofclaim 23 according to Formula I(i) or I(j):

where R¹⁰, R¹², and R¹⁴ are independently hydrogen, halo, or alkyl; R¹,R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ is hydroxy; and R⁴ isheterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionallysubstituted with —NR⁸R^(8′) and where the heteroaryl is optionallysubstituted with alkyl.
 29. The compound of 23 according to Formula I(n)or I(o):

where R⁷ is halo or alkyl; X is halo; R¹⁹ is alkyl; R¹, R², R⁵, and R⁶are hydrogen; R¹⁰, R¹², and R¹⁴ are independently hydrogen or halo; R³is hydroxy; and R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where thealkyl is optionally substituted with —NR⁸R^(8′) and where the heteroarylis optionally substituted with alkyl.
 30. The Compound of 23 accordingto Formula I(p):

where R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R¹⁰ and R¹²are independently hydrogen, halo, or alkyl; R¹⁹ is hydrogen or alkyl; R³is hydroxy; and R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where thealkyl is optionally substituted with —NR⁸R^(8′) and where the heteroarylis optionally substituted with alkyl.
 31. The Compound of 23 accordingto Formula I(q):

where R¹, R¹, R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R¹⁰, R¹², R¹⁴,and R¹⁶ are independently hydrogen or halo; R³ is hydroxy; and R⁴ isheterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionallysubstituted with —NR⁸R^(8′) and where the heteroaryl is optionallysubstituted with alkyl.
 32. The Compound of 23 according to FormulaI(r):

where R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R¹⁰ and R¹²are independently hydrogen, halo, or alkyl; R¹⁴ is hydrogen, halo,alkyl, or amino; R³ is hydroxy; and R⁴ is heterocycloalkyl, alkyl, orheteroaryl, where the alkyl is optionally substituted with —NR⁸R^(8′)and where the heteroaryl is optionally substituted with alkyl.
 33. TheCompound of 23 according to Formula I(s):

R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R¹⁰ and R¹² areindependently hydrogen, halo, or alkyl; R¹⁴ is hydrogen, halo, alkyl, oramino; R³ is hydroxy; and R⁴ is heterocycloalkyl, alkyl, or heteroaryl,where the alkyl is optionally substituted with —NR⁸R^(8′) and where theheteroaryl is optionally substituted with alkyl.
 34. The Compound of 23according to Formula I(u), I(v), I(w), or I(x):

where R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R¹⁰, R¹², andR¹⁴ are independently hydrogen, halo, or alkyl; R³ is hydroxy; and R⁴ isheterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionallysubstituted with —NR⁸R^(8′) and where the heteroaryl is optionallysubstituted with alkyl.
 35. The Compound of claim 1 selected from GroupC and according to Formula I(y) or I(z):

where R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R¹⁰ ishydrogen, halo, or alkyl; R^(10a) is alkyl; R³ is hydroxy; and R⁴ isheterocycloalkyl, alkyl, or heteroaryl, where the alkyl is optionallysubstituted with —NR⁸R^(8′) and where the heteroaryl is optionallysubstituted with alkyl.
 36. The Compound of claim 1 selected from GroupD and according to Formula I(aa) or I(bb):

where R¹, R², R⁵, and R⁶ are hydrogen; X and R⁷ are halo; R³ is hydroxy;and R⁴ is heterocycloalkyl, alkyl, or heteroaryl, where the alkyl isoptionally substituted with —NR⁸R^(8′) and where the heteroaryl isoptionally substituted with alkyl.
 37. The compound according to claim 1selected from the group consisting of:1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}-carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one;6-(azetidin-1-ylcarbonyl)-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(hydroxymethyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(trifluoromethyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-prop-2-en-1-ylazetidin-3-ol;3-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]propane-1,2-diol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-ethylazetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-methylazetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-ethenylazetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one;oximes;[1-({3,4-difluoro-2-[(2-fluoro-4-idophenyl)amino]phenyl}carbonyl)azetidin-3-yl]methanol;1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethane-1,2-diol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-hydroxyazetidine-3-carboxamide;1,1-dimethylethyl[1({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(pyrrolidin-1-ylmethyl)azetidin-3-ol;3-[(diethylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(dimethylamino)methyl]azetidin-3-ol;N-butyl-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-carboxamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-prop-2-en-1-ylazetidine-3-carboxamide;N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-2-methylpropanamide;N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}(carbonyl)azetidin-3-yl]formamide;N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-3,4-dihydroxybutanamide;methyl[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate;N-butyl-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine;1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-amine;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol;(R)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-pyrrolidin-2-ylazetidin-3-ol;(S)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-pyrrolidin-2-ylazetidin-3-ol;3-(aminomethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;3-[(1S)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;3-[(1R)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;(R)-(3-(1-aminopropyl)-3-hydroxyazetidin-1-yl)(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)methanone;(S)-(3-(1-aminopropyl)-3-hydroxyazetidin-1-yl)(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)methanone;1-({3,4-difluoro-2-[(2-fluoro-4-iodphenyl)amino]phenyl}carbonyl)-N-ethylazetidine-3-carboxamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2-hydroxyethyl)azetidine-3-carboxamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2-piperidin-1-ylethyl)azetidine-3-carboxamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-phenylazetidine-3-carboxamide;N-[2-(diethylamino)ethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(morpholin-4-ylmethyl)azetidin-3-ol;1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}piperidin-4-ol;3-{[bis(2-hydroxyethyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-2-(4-methylpiperazin-1-yl)acetamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(4-methylpiperazin-1-yl)methyl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(4-methyl-1,4-diazepan-1-yl)methyl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[methyl(1-methylpyrrolidin-3-yl)amino]methyl}azetidin-3-ol;3-(1,4′-bipiperidin-1′-ylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N,N-bis(2-hydroxyethyl)glycinamide;3-({4-[2-(diethylamino)ethyl]piperazin-1-yl}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}cabonyl-3-{[(2-hydroxyethyl)(methyl)amino]methyl}azetidin-3-ol;N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-2-piperidin-1-ylacetamide;N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N3-(2-hydroxyethyl)-N3-methyl-beta-alaninamide;N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N3,N3-bis(2-hydroxyethyl)-beta-alaninamide;N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N2,N2-bis(2-diethylglycinamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-methylazetidin-3-amine;1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N,N-dimethylpyrrolidin-3-amino;2-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]amino}ethanol;N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]propane-1,3-diamine;3-[(dimethylamino)methyl]-1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-methyl-N-(2-pyridin-2-ylethyl)azetidin-3-amine;N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-N2-methylglycinamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-ethylazetidin-3-amine;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2-methylpropyl)azetidin-3-amine;N-(cyclopropylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine;N-(cyclohexylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine;N-(cyclopentylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine;3-(azetidin-1-ylmethyl)-1-({3,4-difluoro-2-[(2-fluoro-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-[(2,3-dihydroxypropyl)oxy]azetidine-3-carboxamide;2-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-2-yl]methyl}amino)ethanol;N{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-2-yl]methyl}ethane-1,2-diamine;N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]glycinamide;6-({3-[(dimethylamino)methyl]azetidin-1-yl}carbonyl)-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{([1-methylethyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(3,4-dihydroxybutyl)azetidine-3-carboxamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2,3-dihydroxypropyl)azetidine-3-carboxamide;1-({2,4-difluoro-6-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine;1-({4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine;1-({3,4-difluoro-2-[(2-fluo-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidine-3-carboxamide;6-{[3-(aminomethyl)-3-(methyloxy)azetidin-1-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline;N-{([1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}acetamide;2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-[(3-{[(1-methylethyl)amino]methyl}azetidin-1-yl)carbonyl]aniline;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(ethylamino)methyl]azetidin-3-ol;1-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{2-[(1-methylethyl)amino]ethyl}azetidin-3-ol;1-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-hydroxy-1,1-dimethylethyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{1,1-dimethyl-2-[(1-methylethyl)amino]ethyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-methylethyl)amino]methyl}azetidin-3-amine;3-[(cyclopentylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-(2,3-dihydroxypropyl)-3-hydroxyazetidine-3-carboxamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1H-1,2,3-triazol-1-ylmethyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2,2-dimethylpropyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(propylamino)methyl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-methylpropyl)amino]methyl}azetidin-3-ol;3-{[(cyclopropylmethyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(phenylmethyl)amino]methyl}azetidin-3-ol;3-{[(cyclohexylmethyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;3-[(butylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodphenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1-ethylpyrrolidin-2-yl)methyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxyethyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(dimethylamino)ethyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxy-1,1-dimethylethyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(4-methylphenyl)ethyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(prop-2-en-1-ylamino)methyl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(1-methylpyrrolidin-2-yl)ethyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2,3-dihydro-1H-inden-2-ylamino)methyl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(tetrahydrofuran-2-ylmethyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(tetrahydro-2H-pyran-4-yl)ethyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1S,2S)-2-hydroxycyclopentyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1,1-dimethylprop-2-yn-1-yl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3-pyrrolidin-1-ylpropyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1,2-dimethylpropyl)amino]methyl}azetidin-3-ol;1-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(1H-imidazol-4-yl)ethyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[1-methyl-2-(methyloxy)ethyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[3-(ethyloxy)propyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-ethylpropyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3,3-dimethylbutyl)amino]methyl}azetidin-3-ol;ethyl4-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)piperidine-1-carboxylate;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3-methylbutyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-1-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(ethyloxy)ethyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[3-(dimethylamino)propyl]amino}methyl)azetidin-3-ol;3-[(cyclobutylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;3-({[3-(diethylamino)propyl]amino}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[3-(1H-imidazol-1-yl)propyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(methylthio)ethyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[1-(phenylmethyl)piperidin-4-yl]amino}methyl)azetidin-3-ol;3-({[2,2-bis(methyloxy)ethyl]amino}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1,1,3,3-tetramethylbutyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1,1-dimethylpropyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2,2-dihydro-1H-inden-1-ylamino)methyl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[({2-[(phenylmethyl)oxy]cyclopentyl}amino)methy]azetidin-3-ol;3-{[(3-amino-2-hydroxypropyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-hydroxy-1-(phenylmethyl)ethyl]amino}methyl)azetidin-3-ol;3-[(cyclooctylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;3-{[(1-cyclohexylethyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;3-[(cycloheptylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-pyridin-3-ylethyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[3-(methylthio)propyl]amino}methyl)azetidin-3-ol;N-cyclohexyl-N˜2˜-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}-2-methylalaninamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3-hydroxypropyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-pyridin-4-ylethyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[1-(phenylmethyl)pyrrolidin-3-yl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(2-thienyl)ethyl]amino}methyl)azetidin-3-ol;3-[({2-[bis(1-methylethyl)amino]ethyl}amino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(phenyloxy)ethyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(phenylamino)methyl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxypropyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[({2-[(1-methylethyl)oxy]ethyl}amino)methyl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-ethylpiperidin-3-yl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(methyloxy)ethyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-nitropropyl)azetidin-3-ol;3-(1-aminoethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1-methylpiperidin-4-yl)methyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[4-(dimethylamino)butyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-furan-2-ylethyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{1-[(1,1-dimethylethyl)amino]ethyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-ethylbutyl)amino]methyl}azetidin-3-ol;1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}pyrrolidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({(2S)-2-[(methyloxy)methyl]pyrrolidin-1-yl}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxyphenyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(4-hydroxyphenyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3-hydroxyphenyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(phenyloxy)methyl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1r,3r,5R,7R)-tricyclo[3.3.1.1˜3,7˜]dec-2-ylamino]methyl}azetidin-3-ol;3-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)propane-1,2-diol;N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}-L-alanine;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(phenylthio)methyl]azetidin-3-ol;N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}-D-alanine;methylN-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}alaninate;3-[({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)oxy]propane-1,2-diol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-methylbutyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1-methylpropyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-methylbutyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-idophenyl)amino]phenyl}carbonyl)-3-[(pentylamino)methyl]azetidin-3-ol;3-[(1S)-1-aminoethyl]-1-({8-fluoro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)azetidin-3-ol;1-({8-fluoro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-[(1S)-1-(methylamino)ethyl]azetidin-3-ol;3-[(cyclohexylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[1-(ethylamino)ethyl]azetidin-3-ol;3-[(azepan-3-ylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(dimethylamino)-1-methylethyl]amino}methyl)azetidin-3-ol;N-cyclopropyl-1-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)cyclopentanecarboxamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[2-(2,3-dihydro-1H-indol-3-yl)ethyl]amino}methyl)azetidin-3-ol;N˜2˜-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}-N-ethyl-2-methylalaninamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2-methylhydrazino)methyl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-idophenyl)amino]phenyl}carbonyl)-3-[(hydroxyimino)methyl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(methyloxy)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(ethyloxy)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[1-(ethylamino)propyl]azetidin-3-ol;3-[(azetidin-3-ylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl-3-[(1,3-thiazol-2-ylamino)methyl]azetidin-3-ol;3-(1H-benzimidazo-2-yl)-1-({8-fluoro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)azetidin-3-ol;3-(1H-benzimidazol-2-yl)-1-({7-[(4-bromo-2-fluorophenyl)amino]-8-fluoroimidazo[1,2-a]pyridin-6-yl}carbonyl)azetidin-3-ol;1,1-dimethylethyl[3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)propyl]carbamate;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(pyrrolidin-2-ylmethyl)amino]methyl}azetidin-3-ol;1,1-dimethylethyl4-[({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)methyl]piperidine-1-carboxylate;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(2-hydroxyphenyl)methyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(3-hydroxyphenyl)methyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(4-hydroxyphenyl)methyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(4-hydroxybutyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxyethyl)oxy]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1S,2S)-2-hydroxycyclohexyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(1,1-dimethyl-2-pyrrolidin-1-ylethyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1-methyl-1H-imidazol-4-yl)methyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(1-methyl-1H-imidazol-5-yl)methyl]amino}methyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[(2S)-2-(methyloxy)cyclopentyl]amino}methyl)azetidin-3-ol;3-{[1,1′-bi(cyclohexyl)-2-ylamino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[3-(methyloxy)phenyl]amino}methyl)azetidin-3-ol;1-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)cyclopentanecarboxylicacid;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(4-fluorophenyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1,3,5-triazin-2-ylamino)methyl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(trans-4-hydroxycyclohexyl)amino]methyl}azetidin-3-ol;3-[(cyclopent-3-en-1-ylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;N-[4-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)phenyl]acetamide;N-[3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)phenyl]acetamide;1-({3,4-difluoro-2-[(2-fluoro-1-iodophenyl)amino]phenyl}carbonyl)-3-(1-methylpyrrolidin-2-yl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1H-1,2,4-triazol-3-ylamino)methyl]azetidin-3-ol;3-[1-(diethylamino)propyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)-5-(hydroxymethyl)cyclopentane-1,2-diol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-piperidin-2-ylazetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3-fluorophenyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl-3-(1-methylpiperidin-2-yl)azetidin-3-ol;1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}guanidine;1-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}-3-nitroguanidine;N-{[1-ο1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}acetamide;(2R)-N-{1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(piperidin-4-ylmethyl)amino]methyl}azetidin-3-ol;3-{[(3-aminopropyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-1-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[({[2-(4-methylpiperazin-1-yl)phenyl]methyl}amino)methyl]azetidin-3-ol;3-{[(1,1-dimethylethyl)amino]methyl}-1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-hydroxycyclohexyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2,2,3,3,3-pentafluoropropyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3,3,3-trifluoropropyl)amino]methyl}azetidin-3-ol;N-[3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)phenyl]methanesulfonamide;N-{[1-({3,4-difluoro-2-[(2-fluoro-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}methanesulfonamide;3-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)-1H-pyrazol-5-ol;(1R,2S)-4-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)cyclopentane-1,2-diol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[1-(hydroxymethyl)cyclohexyl]amino}methyl)azetidin-3-ol;3-{[(3-chlorophenyl)amino]methyl}-1({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;3-{[(4-chlorophenyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;3-[(5-amino-3-methyl-1H-pyrazol-1-yl)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(5-methyl-1H-pyrazol-3-yl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-ethylpyrrolidin-2-yl)azetidin-3-ol;(2R)-N-{(1S)-1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}-3,3,3-trifluoro-2-(methyloxy)-2-phenylpropanamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[4-(methyloxy)phenyl]amino}methyl)azetidin-3-ol;3-(1-amino-2-methylpropyl)-1-({3,4-difluoro-2-[(2-fluoro-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;3-{[(4-aminophenyl)amino]methyl}-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2hydroxy-2-methylcyclopentyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{1-[(4-hydroxycyclohexyl)amino]ethyl}azetidin-3-ol;methyl(2xi)-2-deoxy-2-({[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}amino)-beta-D-arabino-hexopyranoside;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-pyridin-2-ylazetidin-3-ol;(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-({[1-(hydroxymethyl)cyclopentyl]amino}methyl)azetidin-3-ol;1-cyano-3-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}guanidine;6-({3-[(ethylamino)methyl]-3-fluoroazetidin-1-yl}carbonyl)-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-nitroethyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(3-fluoro-4-hydroxyphenyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{[(2-fluoro-4-hydroxyphenyl)amino]methyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[1-(methylamino)ethyl]azetidin-3-ol;3-(1-aminoethyl)-1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)azetidin-3-ol;1-({8-fluoro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;1-({8-fluoro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-{(1S)-1-[(2-hydroxy-2-methylcyclopentyl)amino]ethyl}azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1H-imidazol-2-yl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1H-pyrrol-2-yl)azetidin-3-ol;N-{[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl}benzenecarboximidamide;3-({[(E)-1-amino-2-nitroethenyl]amino}methyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-methyl-1-nitroethyl)azetidin-3-ol;3-(1-amino-1-methylethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;3-[(1H-benzimidazol-2-ylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1H-imidazol-2-ylamino)methyl]azetidin-3-ol;methyl{1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate;3-(1H-benzimidazol-2-yl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[1-(dimethylamino)ethyl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(pyrimidin-2-ylamino)methyl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(pyridin-2-ylamino)methyl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1-methyl-1H-imidazol-2-yl)azetidin-3-ol;3-(1-aminobutyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({2-fluoro-3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-[(2S)-pyrrolidin-2-yl]azetidin-3-ol;1-({8-fluoro-7-[(2-fluoro-4-iodophenyl)amino]-4-methylcinnolin-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;3-[amino(phenyl)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(5-methyl-1H-imidazol-2-yl)azetidin-3-ol;1,1-dimethylethyl(2S)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate;1-({2-[(4-bromo-2-chlorophenyl)amino]-3,4-difluorophenyl}carbonyl)-3-piperidin-2-ylazetidin-3-ol;3-(1-amino-3-hydroxypropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(1H-imidazol-2-ylmethyl)azetidin-3-ol;3-(1-aminocyclopentyl)-1-({3,4-difluoro-2[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;3-(2-aminocyclohexyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;3-(2-aminocyclopentyl)-1-({3,4-difluoro-2-[(2-fluoro-iodophenyl)amino]phenyl}carbonyl)-azetidin-3-ol;1-({4-fluoro-5-[(2-fluoro4-iodophenyl)amino]-1-methyl-1H-benzimidazol-6-yl}carbonyl)-3-piperidin-2-ylazetidin-3-ol;1-({5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-1-methyl-1H-benzimidazol-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-piperidin-2-ylazetidin-3-ol;1-({2-[(4-bromo-2-fluorophenyl)amino]-3,4-difluorophenyl}carbonyl)-3-piperidin-2-ylazetidin-3-ol;1-({7-[(4-bromo-2-fluorophenyl)amino]-8-fluoroimidazo[1,2-a]pyridin-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(3-methyl-1-nitrobutyl)azetidin-3-ol;3-(2-aminopyrimidin-4-yl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({7-[(4-bromo-2-chlorphenyl)amino]-8-chloroimidazo[1,2-a]pyridin-6-yl}carbonyl)-3-piperidin-2-ylazetidin-3-ol;1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;1-({7-[(4-bromo-2-chlorophenyl)amino]-8-chloroimidazo[1,2-a]pyridin-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;1-{(4-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-1-methyl-1H-benzimidazol-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;3-[(1S)-1-aminoethyl]-1-({5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-1-methyl-1H-benzimidazol-6-yl}carbonyl)azetidin-3-ol;1-({5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-1-methyl-1H-benzimidazo-6-yl}carbonyl)-3-[(1S)-1-(methylamino)ethyl]azetidin-3-ol;4-[(4-bromo-2-fluorophenyl)amino]-3-fluoro-5-({3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}carbonyl)pyridin-2(1H)-one;4-[(2-fluoro-4-iodophenyl)amino]-5-({3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}carbonyl)-1-methylpyridin-2(1H)-one;4-[(2-fluoro-4-iodophenyl)amino]-5-({3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}carbonyl)-1-methylpyridin-2(1H)-one;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1S,2S)-2-hydroxycyclohexyl]azetidin-3-ol;4-[(2-fluoro-4-iodophenyl)amino]-5-({3-hydroxy-3-[(1S)-1-(methylamino)propyl]azetidin-1-yl}carbonyl)-1-methylpyridin-2(1H)-one;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(1S,2R)-2-hydroxycyclohexyl]azetidin-3-ol;5-({3-[(1S)-1-(dimethylamino)ethyl]-3-hydroxyazetidin-1-yl}carbonyl)-4-[(2-fluoro-4-iodophenyl)amino]-1-methylpyridin-2(1H)-one;4-[(2-fluoro-4-iodophenyl)amino]-5-({3-hydroxy-3-[(methylamino)methyl]azetidin-1-yl}carbonyl)-1-methylpyridin-2(1H)-one;5-{[3-(1H-benzimidazol-2-yl)-3-hydroxyazetidin-1-yl]carbonyl}-4-[(4-bromo-2-fluorophenyl)amino]-1-methylpyridin-2(1H)-one;4-[(4-bromo-2-fluorophenyl)amino]-5-{[3-hydroxy-3-(1-methyl-1H-benzimidazol-2-yl)azetidin-1-yl]carbonyl}-1-methylpyridin-2(1H)-one;4-[(4-bromo-2-fluorophenyl)amino]-5-({3-hydroxy-3-[(2S)-pyrrolidin-2-yl]azetidin-1-yl}carbonyl)-1-methylpyridin-2(1H)-one;1-({3-fluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;1-({4-fluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;1-({6-[(4-bromo-2-chlorophenyl)amino]-7-fluoro-3-methyl-1,2-benzisoxazol-5-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(6-methylpiperidin-2-yl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-piperidin-2-ylazetidin-3-ol;5-[(2-fluoro-4-iodophenyl)amino]-6-({3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}carbonyl)-2-methylpyridazin-3(2H)-one;5-[(4-bromo-2-chlorophenyl)amino]-6-({3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}carbonyl)-2-methylpyridazin-3(2H)-one;5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-6-({3-hydroxy-3-[(2S)-pyrrolidin-2-yl]azetidin-1-yl}carbonyl)-2--methylpyridazin-3(2H)-one;5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-6-({3-hydroxy-3-[(2R)-pyrrolidin-2-yl]azetidin-1-yl}carbonyl)-2-methylpyridazin-3(2H)-one;6-({3-[(1S)-1-aminoethyl]-3-hydroxyazetidin-1-yl}carbonyl)-5-[(2-fluoro-4-iodophenyl)amino]-2-methylpyridazin-3(2H)-one;6-({3-[(1S)-1-aminoethyl]-3-hydroxyazetidin-1-yl}carbonyl)-5-[(4-fluoro-2-chlorophenyl)amino]-2-methylpyridazin-3(2H)-one;5-[(4-bromo-2-chlorophenyl)amino]-6-{[3-((1S)-1-{[(3R,4S)-3,4-dihydroxycyclopentyl]amino}ethyl)-3-hydroxyazetidin-1-yl]carbonyl}-2-methylpyridazin-3(2H)-one;5-[4-bromo-2-fluorophenyl)amino]-6-[(3-hydroxy-3-{(1S)-1-[(2-hydroxy-2-methylcyclopentyl)amino]propyl}azetidin-1-yl)carbonyl]-2-methylpyridazin-3(2H)-one;6-({3-[(1S)-1-aminopropyl]-3-hydroxyazetidin-1-yl}carbonyl)-5-[(4-bromo-2-fluorophenyl)amino]-2-methylpyridazin-3(2H)-one;6-{[3-(1H-benzimidazol-2-yl)-3-hydroxyazetidin-1-yl]carbonyl}-5-[(2-fluoro-4-iodophenyl)amino]-2-methylpyridazin-3(2H)-one;5-[(2-fluoro-4-iodophenyl)amino]-6-{[3-hydroxy-3-(1-methyl-1H-benzimidazol-2-yl)azetidin-1-yl]carbonyl}-2-methylpyridazin-3(2H)-one;1-({2-fluoro-3-[(2-fluoro4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;1-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;1-({2-fluoro-3-[(2-fluoro-4-bromophenyl)amino]pyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-oil;3-[(1S)-1-aminopropyl]-1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)azetidin-3-ol;1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-[(1S)-1-(methylamino)propyl]azetidin-3-ol;(1R,2S)-4-({(1S)-1-[1-({2-fluoro-3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]propyl}amino)cyclopentane-1,2-diol;1-({7-[(4-bromo-2-chlorophenyl)amino]-8-fluoro-4-methylcinnolin-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;1-({7-[(4-bromo-2-fluorophenyl)amino]-8-fluoro-4-methylcinnolin-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;3-[(1S)-1-aminoethyl]-1-({7-[(4-bromo-2-fluorophenyl)amino]cinnolin-6-yl}carbonyl)azetidin-3-ol;1-({7-[(4-bromo-2-fluorophenyl)amino]cinnolin-6-yl}carbonyl)-3-{(1S)-1-[(2-hydroxy-2-methylcyclopentyl)amino]ethyl}azetidin-3-ol;1-({7-[(4-bromo-2-fluorophenyl)amino]cinnolin-6-yl}carbonyl)-3-[(1S)-1-(dimethylamino)ethyl]azetidin-3-ol;3-[(1S)-1-aminoethyl]-1-({5-[(2-fluoro-4-iodophenyl)amino]-1H-1,2,3-benzotriazol-6-yl}carbonyl)azetidin-3-ol;3-[(1S)-1-(dimethylamino)ethyl]-1-({5-[(2-fluoro-4-iodophenyl)amino]-1-methyl-1H-1,2,3-benzotriazol-6-yl}carbonyl)azetidin-3-ol;1-({5-[(2-fluoro-4-iodophenyl)amino]-1H-1,2,3-benzotriazol-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;1-({5-[(2-fluoro-4-iodophenyl)amino]-1-methyl-1H-1,2,3-benzotriazol-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;1-({5-[(2-fluoro-4-iodophenyl)amino]-1H-1,2,3-benzotriazol-6-yl}carbonyl)-3-{(1S)-1-[(2-hydroxy-2-methylcyclopentyl)amino]ethyl}azetidin-3-ol;3-[(1S)-1-aminoethyl]-1-({4-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-1H-1,2,3-benzotriazol-6-yl}carbonyl)azetidin-3-ol;1-({4-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-1H-1,2,3-benzotriazol-6-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;5-({3-[(1S)-1-aminoethyl]-3-hydroxyazetidin-1-yl}carbonyl)-6-[(2-fluoro-4-iodophenyl)amino]pyrimidin-2(1H)-one;6-[(2-fluoro-4-iodophenyl)amino]-5-({3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-yl}carbonyl)pyrimidin-2(1H)-one;4-[(2-fluoro-4-iodophenyl)amino]-5-({3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl}carbonyl)pyrimidin-2(1H)-one;and5-({3-[(1S)-1-aminoethyl]-3-hydroxyazetidin-1-yl}carbonyl)-4-[(2-fluoro-4-iodophenyl)amino]pyrimidin-2(1H)-one.38. A pharmaceutical composition comprising a compound of Formula I, ora pharmaceutically acceptable salt or solvate therof, and apharmaceutically acceptable carrier, excipient, or diluent.
 39. A methodof inhibiting MEK comprising administering to a patient atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof, and optionally apharmaceutically acceptable carrier, excipient, or diluent.
 40. A methodof treating a disease, disorder, or syndrome which method comprisesadministering to a patient a compound of Formula I or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of Formula Iand a pharmaceutically acceptable carrier, excipient, or diluent. 41.The method of claim 40 where the disease is a proliferative disease. 42.A method of treating cancer which method comprises administering to apatient a therapeutically effective amount of a compound of Formula I ora pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula I and a pharmaceutically acceptable carrier,excipient, or diluent.
 43. The method of claim 42 where the cancer ismelanoma, colon cancer, rectal cancer, pancreatic cancer, breast cancer,non-small cell lung cancer, small cell lung cancer, papillary andanaplastic thyroid cancer, endometrial cancer, or ovarian cancer.